Genetic predispositions can shape the gut microbiome, which in turn modulates host gene expression and impacts host physiology. The complex interplay between host genetics and the gut microbiome likely contributes to the development of neuropsychiatric disorders, yet the mechanisms behind these interactions remain largely unexplored. In this study, we investigated the gut microbiota in Negr1 knockout (KO) mice, which exhibit anxiety- and depression-like behaviors, as NEGR1 (neuronal growth regulator 1) is a cell adhesion molecule linked to neuronal development and neuropsychiatric disorders. Our findings show significant early-life alterations in the gut microbiota composition of Negr1 KO mice, most notably a marked reduction in Akkermansia spp. along with reduced dendritic arborization and spine density in the nucleus accumbens (NAc) and the dentate gyrus (DG) of the hippocampus. Remarkably, daily administration of an Akkermansia strain isolated from wild-type mice reversed the neuronal structural abnormalities and ameliorated anxiety- and depression-like behaviors in Negr1 KO mice. Transcriptomic profiling revealed upregulation of mitochondrial genome-encoded genes in the NAc and hippocampus of Negr1 KO mice, along with a predisposition toward a pro-inflammatory state in the colon of Negr1 KO mice. The Akkermansia supplementation downregulated these mitochondrial genes in the NAc and hippocampus and upregulated genes involved in T cell activation and immune homeostasis in the colon. These findings demonstrate a novel gene-microbiome interaction in the pathophysiology of Negr1 KO mice, positioning Akkermansia spp. as a key mediator that improves neuronal atrophy and modulates anxiety- and depression-like behaviors. Our study provides compelling evidence for bidirectional interactions between host genetics and the gut microbiome in modulating neuropsychiatric phenotypes, offering new insights for addressing genetically influenced mental disorders.

The outcomes of traumatic brain injury (TBI) are closely linked to the strength of mechanical loads applied to the head. However, the same mechanical load can lead to significant variations in injury outcomes depending on the location of impact. To compare the acute-phase behavioral and pathological effects of different impact locations on TBI outcomes, we conducted a closed head injury experimental study using male rats subjected to cranial vertex and temporal lobe impacts. The rats were injured by an impactor according to the experimental protocol established using the L4 (23) orthogonal table, and the behavioral and pathological outcomes were assessed. The contribution rates of impact location and strength to TBI were quantified using Analysis of Variance. The results indicated that impact strength played a dominant role in TBI and showed a positive correlation, while the role of impact location in TBI cannot be ignored. Behaviorally, cranial vertex impacts led to more severe coma, motor, memory, and anxiety deficits. Pathologically, cranial vertex impacts caused more severe diffuse axonal injury in the corpus callosum and brainstem. In the left hippocampus and amygdala, cell loss due to cranial vertex impacts was more pronounced than that caused by temporal lobe impacts, whereas the opposite was true on the right side. Notably, the pathological changes observed in the left (non-impact) hippocampus and amygdala due to temporal lobe impacts showed a stronger linear correlation with behavioral outcomes, suggesting that damage to the left side has greater predictive power for behavioral deficits. This suggests that the impact location is an important factor affecting TBI and should be considered in the study.

The rTg4510 and PS19 mouse models are widely used in tauopathy research. Alzheimer's disease (AD) is the most prevalent among tauopathies. Behavioural tests are frequently used to assess emotional, cognitive, and motor behaviours in mouse models of AD. Cognitive deficits begin to manifest in rTg4510 mice around 3 months of age and in PS19 mice around 6 months. However, it's widely recognized that behavioural outcomes can vary due to environmental factors, health status, and husbandry practices, causing phenotypic differences between facilities. This study aims to consolidate current knowledge of the behavioural phenotypes of these two mouse models. We conducted a comprehensive literature review using keyword searches with Boolean operators across databases up to January 2024. Additional studies were included from manual searches. A total of 23 articles were reviewed for rTg4510 mice and 52 for PS19 mice. We extracted methodological details and key findings from each study. Results for rTg4510 mice show consistent findings regarding locomotion, memory and learning, and neurological dysfunction. However, the limited studies on motor and balance behaviour revealed no significant differences, while anxiety-like behaviour showed some inconsistencies. PS19 mice demonstrate more robust results for anxiety-like behaviour, memory and learning, and locomotion, while findings for balance and coordination are more inconsistent. Although there is overall coherence in certain aspects of the behavioural profiles of these tauopathy mouse models, it is crucial to recognize experimental heterogeneity and profile behavioural baselines to optimize the testing of both genetic and pharmacological interventions.

In eukaryotic cells, organelles in the secretory, lysosomal, and endocytic pathways actively exchange biological materials with each other through intracellular membrane trafficking, which is the process of transporting the cargo of proteins, lipids, and other molecules to appropriate compartments via transport vesicles or intermediates. These processes are strictly regulated by various small GTPases such as the RAS-like in rat brain (RAB) protein family, which is the largest subfamily of the RAS superfamily. Dysfunction of membrane trafficking affects tissue homeostasis and leads to a wide range of diseases, including neurological disorders and neurodegenerative diseases. Therefore, it is important to understand the physiological and pathological roles of RAB proteins in brain function. RAB35, a member of the RAB family, is an evolutionarily conserved protein in metazoans. A wide range of studies using cultured mammalian cells and model organisms have revealed that RAB35 mediates various processes such as cytokinesis, endocytic recycling, actin bundling, and cell migration. RAB35 is also involved in neurite outgrowth and turnover of synaptic vesicles. We generated brain-specific Rab35 knockout mice to study the physiological roles of RAB35 in brain development and function. These mice exhibited defects in anxiety-related behaviors and spatial memory. Strikingly, RAB35 is required for the precise positioning of pyramidal neurons during hippocampal development, and thereby for normal hippocampal lamination. In contrast, layer formation in the cerebral cortex occurred superficially, even in the absence of RAB35, suggesting a predominant role for RAB35 in hippocampal development rather than in cerebral cortex development. Recent studies have suggested an association between RAB35 and neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. In this review, we provide an overview of the current understanding of subcellular functions of RAB35. We also provide insights into the physiological role of RAB35 in mammalian brain development and function, and discuss the involvement of RAB35 dysfunction in neurodegenerative diseases.

Depression and anxiety are comorbid with diabetes. Diabetes and depression have a bidirectional relationship. In this study, Linezolid was evaluated for the treatment of depression and anxiety comorbid with T2DM. Linezolid may exhibit antidepressant and anxiolytic-like effects via modulation of MAO enzyme activity. In the study, male Swiss Albino mice were divided into 9 groups (n = 70). Group 1 (normal control); Group 2 diabetes control (DC); Group 3, 4, and 5 (low, intermediate, high dose of Linezolid; LDL, IDL and HDL); Group 6 [DC + Paroxetine (PAR)], Group 7 [DC + Metformin (MET)]; Group 8 (DC + LDL + PAR); Group 9 (DC + LDL + PAR + MET). Except for the normal control group, all the other groups were induced with T2DM with Streptozotocin (50 mg/kg, i.p.) and Nicotinamide (120 mg/kg, i.p.). Mice showed glucose levels of more than 160 mg/dl were taken in the study. Following a 14-day treatment, behavioral and biochemical assessments were done using the FST, TST, EPM, and OFT, and blood glucose, plasma corticosterone, brain TNF-α and serotonin were measured. Group 3 to 9 showed their activity in behavioral models of depression and anxiety such as FST, TST, OFT, and EPM. The treatment groups (Groups 3 to 9) also have shown a significant (p < 0.05) decrease in blood glucose, plasma corticosterone, and brain TNF-α levels with respect to DC, while serotonin levels are increased in Groups 5, 8 & 9. The above findings suggest the beneficial effects of Linezolid in the treatment of depression and anxiety comorbid with T2DM.

Binge eating is defined as eating abnormally large amounts in a brief period of time. Many animal studies have examined the behavioural and physiological effects of binge eating of high-fat, high-sugar foods to model the consequences of human binge eating. The present systematic review of 199 rodent studies sought to identify the behavioural and physiological consequences of binge eating and determine whether changes were specific to binge eating or to general effects of exposure to a palatable diet. A meta-analysis of 18 rodent studies revealed that binge eating produces greater anxiety-like behaviour on the Elevated Plus-Maze with a small effect size and significant funnel plot asymmetry, suggesting that the true effect size is overestimated. A history of binge-like access generally increases progressive ratio breakpoint for the binged food, without altering 'liking' as measured by lick microstructure, suggesting that dissociable effects on 'wanting' but not 'liking' accompany binge eating behaviour and contribute to its persistence. Binge eating appears to enhance compulsive food-seeking behaviour and prevent stress-induced reductions in intake but does not appear to alter depression-like behaviour or locomotor activity. Notably, binge eating may produce comparable metabolic impairments to those observed after extended continuous exposure to a palatable diet despite no overall effects on body weight outcomes in most studies.

It has been suggested that Alzheimer's disease (AD), a progressive neurological condition, can potentially be treated through epigenetic means by targeting histone deacetylases (HDACs), enzymes that regulate gene expression. In this study, we investigated the molecular mechanisms of Bufexamac, in an animal model of AD. Bufexamac specifically targets Class IIb HDACs, which are particularly relevant in the context of neuroinflammation and neurodegeneration. This selectivity may reduce off-target effects commonly associated with broader-spectrum HDAC inhibitors, such as pan-HDAC inhibitors, which can affect multiple HDAC classes and potentially lead to undesirable side effects. Male rats injected with Aβ25-35 for AD-like symptoms were treated with 20 μg/rat Bufexamac for 8 days. Cognitive function, depression, and anxiety were assessed through behavioral tests, while Western blotting, H&E staining, and ELISA were used to detect protein expression, morphological changes, and enzyme activity. Bufexamac treatment markedly improved cognitive and behavioral impairments in Aβ-injected rats and regulated the key proteins related to neuroinflammation (GFAP, Iba1), histone, and α-tubulin acetylation. Simultaneously, it decreased the expression of proteins in the stromal interaction molecule (STIM) pathway. Furthermore, Bufexamac lowered the activity of monoamine oxidase enzymes, elevated the count of healthy neurons, and ameliorated neuronal structure in the hippocampus. Overall, these findings suggest that Bufexamac could be a more targeted therapy for AD than other non-selective HDAC inhibitors, which often have diverse functions and potential side effects. Bufexamac enhances cognitive function and alleviates depression and anxiety by regulating proteins related to neuroinflammation, histone, and α-tubulin acetylation, as well as modulating STIM levels and MAO activity.

Paclitaxel (PTX), a widely used chemotherapeutic agent, causes both peripheral and central neurotoxicity, leading to significant behavioral impairments. However, inadequate literature is available on PTX-induced neurobehavioral sequelae associated with anxiety, depression, and cognition in adults during and after chemotherapy. Therefore, the present study aimed to investigate neurobehavioral impairments in adult female rats following PTX exposure, with a specific focus on anxiety-like behaviors and cognitive functions such as learning and memory. In this study, we used adult female Wistar rats aged 10-12 weeks (average weight: 180 ± 5 g) and administered clinically relevant therapeutic doses of PTX (1.6 and 3.2 mg/kg body weight) intravenously once weekly for 6 weeks, simulating the clinical chemotherapy regimen. Neurobehavioral assessments were conducted after the first and sixth doses of PTX using validated mazes, including the photoactometer, open-field maze, elevated plus-maze (EPM; for anxiety-like behaviors), and the step-down latency test (SDL; for cognitive performance). Neurobehavioral patterns were recorded using autotracking software (ANY-maze, Stoelting Co., Wood Dale, Illinois, USA). Our findings revealed substantially reduced locomotor activity in the photoactometer, increased anxiety-like behaviors with amplified fear emotionality in the open-field and EPM tests, and memory impairment in the SDL test. These results suggest that the manifestation of anxiogenic and cognitive behavioral changes is associated with the administration of a higher dose (3.2 mg/kg) of PTX. In conclusion, our study indicates that PTX causes significant neurobehavioral impairments in rats after exposure to equivalent therapeutic doses of PTX.

Cannabinoid receptor agonists increase eating in a dose-dependent manner. However, the behavioral mechanisms by which cannabinoids modulate food intake control aren't clear, particularly in females. We utilized a rodent model of cannabinoid administration modeling a common route of cannabinoid consumption in humans: edibles. Herein, we administered the dual cannabinoid receptor agonist CP55940 in edible form to female rats and observed acute increases in standard chow intake due to an increase in meal size with no change in meal number. We further observed that the hyperphagic dose of edible CP55940 increases impulsive responding for sucrose, but this did not coincide with changes in motivation for sucrose. Finally, cannabinoids can affect anxiety-like behavior, but the acutely hyperphagic dose used in our studies had no effect on anxiety-like behavior. We conclude that edible cannabinoid administration delays satiation and increases impulsive eating behavior without impacting food motivation, potentially by reducing inhibitory control.

Abusive head trauma (AHT) resulting from violent shaking and whiplash-induced brain injury by a caregiver, is the leading cause of abusive mortality and morbidity in children. Cerebral oedema is common in survivors of AHT. While many children may initially appear behaviourally asymptomatic or present with non-specific symptoms following the AHT, deficits often emerge later in childhood. Additionally, AHTs are frequently repetitive, with a single child likely to experience multiple AHTs. Despite the prevalence of AHT, the mechanisms that lead to brain pathology and the latent emergence of behavioural deficits are poorly understood, and there is a paucity of preclinical, small animal models to investigate the biology and cumulative effects of repetitive injuries. This study aimed to develop a preclinical model of repetitive AHT and subsequently examine alterations in gene expression, cell types, and early adolescent behaviour. Mice were placed on a 400 rpm shaking device for 60s. This was repeated one, three, or five times throughout the neonatal development period (postnatal days (P)8-12). Injured mice initially displayed no overt behavioural changes compared to uninjured controls; however, in adolescence (P40-45) they later developed deficits in socialisation and thermal nociception. Further, alterations in the expression of genes involved in growth, cell damage, and development were observed in the brains of injured mice, along with an increase in white matter cells and evidence of blood-brain barrier leakage. This novel preclinical model of AHT provides a valuable platform for exploring diagnostic biomarkers and potential therapeutic interventions for children with an AHT.

Chronic inflammatory pain is a top priority for arthritis patients seeking medical care. Despite the availability of NSAIDs and glucocorticoids, pain management becomes increasingly challenging due to central and peripheral sensitization. Previous studies have shown that Matrix metalloproteinase 2 (MMP2) promotes neuroinflammation by cleaving extracellular matrix proteins and activating pro-inflammatory cytokines. Folic acid acts as a promising candidate for the treatment of neuroinflammatory diseases due to its neuroprotective effects. However, the role of folic acid in inflammatory pain remains unclear. This study investigated the analgesic mechanisms of folic acid in inflammatory pain. Adult rats underwent inflammatory pain by injecting complete freund's adjuvant (CFA) into the right hindpaw. Behavioral tests were used to assess the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). The results demonstrated that CFA injection induced abnormal mechanical and thermal pain and increased MMP2 expression in L3-L5 DRG and SDH of CFA rats. MMP2 was mainly expressed in neurons rather than glial cells in L3-L5 DRG of CFA rats. We further discovered that MMP2 inhibitor auraptene or knockdown alleviated inflammatory pain in CFA rats. Interestingly, we observed that long-term folic acid treatment reversed MMP2 overexpression, resulting in sustained relief of chronic inflammatory pain. Consistently, long-term folic acid treatment also relieved pain-induced anxiety. These results indicated that folic acid had a protective role in chronic inflammatory pain and pain-induced anxiety by repressing MMP2 expression. Folic acid or auraptene might be promising therapeutic options for the treatment of chronic inflammatory pain.

The interaction between liver and brain health is an emerging complex relationship implicated in Alzheimer's disease (AD). Divergence in aerobic capacity influences liver and brain health independently; however, whether these factors converge to influence AD risk is mechanistically unknown. Bile acid metabolism has been implicated as a link between liver and brain health and is modulated by aerobic capacity. Here, we examined rats selectively bred for high vs. low intrinsic aerobic capacity [high and low-capacity runner (HCR or LCR)] on indices of hepatic metabolism and brain health following a chronic low-fat, high-fat, or high-fat diet with bile acid sequestrant from 6 to 12 months of age. Pre- and post-diet measures included learning, memory, and brain volume metabolite levels. We additionally quantified brain and liver Aβ and proteins associated with Aβ production and clearance, as well as liver and brain mitochondrial energetics and liver bile acid species. We found that not only did aerobic capacity and diet influence mitochondrial function, but also it modified Aβ levels across the liver and brain. Additionally, aerobic capacity and diet altered bile acid profiles and brain hippocampal metabolite levels. The addition of bile acid sequestrant lowered brain Aβ levels in a sexually dimorphic manner. Aerobic capacity but not diet altered cognitive outcomes. Our results indicate that aerobic capacity and diet-induced liver health alterations modulate brain health with respect to metabolism and AD-like pathologies, whereas a stimulation of faecal bile acid loss could have positive effects on lowering brain Aβ. KEY POINTS: Aerobic capacity and diet-induced alterations to liver function alter liver bile acid species and faecal energy loss. Aerobic capacity and diet alter both brain and liver Aβ homeostasis. Aerobic capacity modulates brain and hippocampal volume in addition to brain metabolism. Aerobic capacity influences learning in middle-aged rats.

Microdosing, the repeated use of psychedelic substances at low doses, is growing in popularity among recreational consumers. While this practice is associated with many benefits to mood, well-being and health, research in this area is in its early stages and predominantly centered on human applications. In this narrative review, we synthesize the findings from studies investigating the effects of microdosing on the behaviors of three animal species: rats, mice, and zebrafish. A total of 12 studies were identified that implemented a microdosing regimen of LSD, psilocybin, or DMT in these animal models. Overall, microdosing caused little changes in behaviors associated with anxiety- and depressive-like states. Moreover, while microdosing was well-tolerated across species, further research is needed to capture specific safety concerns. Finally, we critically appraise the studies included in this review based on their methodologies and discuss further avenues of research to advance the preclinical literature on psychedelic microdosing. Specifically, we recommend that future research prioritize the replication of existing findings to inform the development of robust study designs and dosing protocols, as well as establish standardized methodologies to enable effective comparisons across different animal models. Furthermore, future investigations should explore the therapeutic potential of mescaline microdosing, examine sex-dependent effects, and extend research to additional models of psychiatric conditions, including those related to obsessive-compulsive disorder and post-traumatic stress disorder.

Anxiety symptoms are commonly observed in individuals with inflammatory bowel disease (IBD), but the mechanistic link between IBD and comorbid anxiety remains incompletely understood. Our previous study revealed that vagal gut-brain signaling contributes to driving comorbid anxiety-like behaviors in dextran sulfate sodium (DSS)-induced colitis mice, but how vagus nerve senses and transmits information to the brain in response to changes in the colonic microenvironment following DSS treatment remain elusive. Here, we identify a critical contribution of pro-inflammatory CD86+ macrophages to activate gut-innervating vagal afferents and ultimately drive anxiety-like behaviors in DSS-treated mice. An increased number of F4/80+ macrophages accumulated closely with gut-innervating vagal afferent fibers following DSS treatment. Depletion of macrophages alleviated DSS-induced anxiety-like behaviors, whereas peripheral delivery of lipopolysaccharide-activated M1 macrophages promoted anxiety-like behaviors, which were prevented by bilateral vagal afferent ablation. Moreover, differential expression levels of anxiety-like behaviors were positively correlated with neuronal activity changes in the nucleus tractus solitarius, locus coeruleus, and basolateral amygdala. Finally, treatment with either anti-α4β7 integrin antagonist vedolizumab or neutralizing anti-interleukin-1β monoclonal antibody effectively alleviated DSS-induced anxiety-like behaviors. Collectively, these findings unravel a mechanism of macrophage-to-vagus nerve communication via cytokine signaling responsible for comorbid anxiety associated with experimental colitis and suggest that pro-inflammatory CD86+ macrophages may represent a potential therapeutic target for psychological comorbidities in patients with IBD.

Ischemic stroke is a leading cause of death and disability worldwide. Survivors face disability and psychiatric sequelae resulting from ischemia-induced cell death and associated neuroinflammation, and oxidative stress. Herbal medicines have been shown to elicit neuroprotective effects following stroke due to their anti-inflammatory and antioxidant effects. Preliminary evidence suggests that Ayahuasca (AYA), a decoction made from the vine Banisteriopsis caapi containing β-carbolines and the shrub Psychotria viridis containing N, N-Dimethyltryptamine, might attenuate ischemia-induced neuroinflammation and oxidative stress. Therefore, in this study we investigated the putative protective effects of AYA in the middle cerebral artery occlusion (MCAO) model of ischemic stroke.

Wistar rats were subjected to the MCAO stroke model or sham surgery on day 0. After 24-h, rats were treated for three days with AYA (2 and 4 mL/kg, gavage) or saline. Neurological score was assessed for 72-h post-stroke. Rats were tested in the elevated plus maze, open field, and novel object recognition tests to assess locomotion, anxiety-like behavior, and recognition memory. Interleukin (IL)-6, IL-10 myeloperoxidase (MPO) activity, and the nitrite/nitrate (N/N) concentrations were determined in the prefrontal cortex (PFC), hippocampus (HPC), hypothalamus (HYP) and cortex. as markers of inflammation. Oxidative stress was quantified in the same brain areas as measured by the levels of thiobarbituric acid reactive species (TBARS), protein carbonylation, and superoxide dismutase (SOD), and catalase (CAT) activity. Mitochondrial metabolism was assessed quantifying the activity of complex 1(CI), CII, citrate synthase (CS), succinate dehydrogenase (SDH), and creatine kinase (CK).

No differences were observed regarding neurological deficits, locomotion, anxiety-like behavior, and recognition memory. However, AYA reversed the stroke-induced increase in IL-6 levels in the PFC and the HPC, IL-10 in the PFC, HPC, and HYP, MPO activity in the PFC, and N/N concentration and CAT activity in the HYP. Moreover, AYA decreased TBARS levels in the PFC and HPC and brain-derived neurotrophic factor (BDNF) in the PFC, and increased SOD activity in the cortex. Lastly, AYA increased CI activity in the HPC and cortex and decreased SDH and CK activity in the HPC.

AYA administration following ischemic stroke modulates oxidative stress and neuroinflammation in the PFC, HPC, and HYP. Despite no significant improvements in neurological or behavioral scores, these molecular changes suggest a neuroprotective role of AYA. Future studies should explore the timing of AYA treatment and putative long-term effects on functional recovery, as well as its potential in other brain regions critical for cognitive and motor functions.

Actin cytoskeleton dynamics is essential for proper nervous system development and function. A conserved set of neuronal-specific microexons influences multiple aspects of neurobiology; however, their roles in regulating the actin cytoskeleton are unknown. Here, we study a microexon in DAAM1, a formin-homology-2 (FH2) domain protein involved in actin reorganization. Microexon inclusion extends the linker region of the DAAM1 FH2 domain, altering actin polymerization. Genomic deletion of the microexon leads to neuritogenesis defects and increased calcium influx in differentiated neurons. Mice with this deletion exhibit postsynaptic defects, fewer immature dendritic spines, impaired long-term potentiation, and deficits in memory formation. These phenotypes are associated with increased RHOA/ROCK signaling, which regulates actin-cytoskeleton dynamics, and are partially rescued by treatment with a ROCK inhibitor. This study highlights the role of a conserved neuronal microexon in regulating actin dynamics and cognitive functioning.

Anxiety Disorder is a common neurological disorder for which ubiquitous environmental endocrine disruptors may be risk factors. 17β-trenbolone (17-TB) has been recognized as a potential environmental endocrine disruptor and its neurotoxic effects have attracted attention. Tachykinin receptor 3 (TACR3), a G protein-coupled receptor involved in pubertal anxiety, and its underlying neural mechanisms remain enigmatic. Therefore, this study investigated the possible relationship between 17-TB and TACR3, testosterone (T), and synaptic plasticity. Our results showed that adolescent male Balb/c mice developed significant anxiety-like behavior after four weeks of exposure to environmentally relevant concentrations of 17-TB (100 μg/kg/day). Transcriptomic RNA-Seq results showed that 17-TB affected abnormal synaptic transmission signals in the hippocampus. Electrophysiological results showed that 17-TB reduced the activity of hippocampal dentate gyrus (DG) neurons and led to the downregulation of hippocampal TACR3 and T levels. In addition, Western blot, immunohistochemistry, ELISA, and qRT-PCR showed that 17-TB exposure led to the downregulation of key hippocampal synaptic proteins PSD95, Gephyrin, and Syn, and induced a metabolic imbalance in glutamate (Glu)/GABA signaling, affecting dopamine signaling. Interestingly, testosterone supplementation (10 mg/kg/day) was effective in ameliorating the above phenomena and alleviating anxiety-like behaviors. These results suggest that 17-TB modulates anxiety-related synaptic plasticity by regulating hippocampal TACR3 and T interactions in vivo. In conclusion, our study contributes to understanding the neurobehavioral and potential mechanistic effects of environmental 17-TB exposure in mammals. It alerts the public to the health risks of chemicals to mammals and suggests new research directions and potential therapeutic targets.

The growing interest in healthy diets has led to increased consumption of natural products such as stevia. Pregnant females, who often consume high amounts of non-caloric sweeteners, are particularly vulnerable. Given the limited health guidelines on stevia, evaluating its effects on this population and their offspring is essential.

This study assessed the impact of early, continuous exposure to an aqueous extract of Stevia rebaudiana Bertoni (Asteraceae) on female rat reproductive health, anxiety, sexual behavior, and progeny outcomes.

Female Sprague-Dawley rats (PND21) were assigned to a control group (CON, water) or a stevia group (STE). In experiment 1, estrous cycles were monitored via vaginal smears (CON, n = 6/assay; STE, n = 14/assay). Anxiety-like behavior was assessed using the elevated plus maze test, and sexual behavior was evaluated through the partner preference test (CON, n = 4/assay; STE, n = 4/assay). Pregnancy rate, duration, litter size, sex ratio, and offspring survival were also assessed. In experiment 2, stevia administration began 5, 10, 15, or 50 d before mating, and the same reproductive parameters were evaluated. Statistical analyses were performed using a Student's t-test, repeated measures analysis of variance (RM-ANOVA), and one-way analysis of variance (ANOVA) with Fisher's Protected Least Significant Difference post-hoc test.

The STE group exhibited disrupted estrous cycles, reduced pregnancy rates, and smaller litters (with notably fewer males). Body weight was significantly lower in the STE group during the third week of pregnancy. There were no significant differences in food or beverage intake. Behaviorally, the STE group showed decreased sexual partner preference, lower anxiety, and increased risk assessment behavior. Prolonged premating exposure to stevia was associated with extended pregnancy duration, smaller litters, and higher pup weights at PND1.

Stevia disrupted fertility, reducing pregnancy rates, litter size, and male offspring, while extending gestation. Prolonged exposure worsened these effects, highlighting stevia's impact on reproduction and prenatal development. These findings underscore the need for improved health guidelines for vulnerable populations.

Schizophrenia is believed to arise because of the interaction of early abnormal neurodevelopment with environmental insults during key developmental stages later in life. Furthermore, disrupted circadian rhythms are reported in patients, and circadian disruption is associated with increased symptom severity, hinting at its role as a risk factor. Using the neonatal ventral hippocampal lesion mouse model, we aimed to assess the interaction between disrupted ventral hippocampal development with circadian disruption during adolescence in affecting behavior in male and female C57BL/6N mice. After conducting a series of behavioral tests, we found that the neonatal ventral hippocampal lesion and chronic jet lag during adolescence synergistically led to increased anxiety-like behavior in males. In females, the lesion prevented increased social preference caused by chronic jet lag and led to increased anxiety-like behavior. Mice were then moved to running wheel cages to measure their locomotor activity rhythms. We found that the lesioned male mice exposed to chronic jet lag exhibited fragmented rhythms under constant darkness. Moreover, lesioned male and female mice, especially those exposed to chronic jet lag, had reduced activity counts under constant light. These findings highlight that the interaction of abnormal neurodevelopment in areas relevant to schizophrenia with circadian disruption during adolescence results in lasting behavioral changes in a sex-dependent manner in mice.

Due to low efficacy and delayed therapeutic effect of drugs currently used in the therapy of depression in adolescent population, a lot of effort has been put into finding new substances using alternative target points that could support treatment with traditional antidepressive drugs. Cannabidiol, compound derived from Cannabis sativa may have therapeutic potential in depressive disorders. This study aimed to investigate whether combined administration of escitalopram with cannabidiol in ineffective doses, will provide better or similar effects in behavioral tests compared to escitalopram in an effective dose in adolescent maternally separated rats. Maternal separation has been used as a form of early life adversity. The pups were separated from their dams for 360 min daily from postnatal day (PND) 2 until PND 15. Later, escitalopram (15 or 5 mg/kg) or vehicle were administered ip. in a subacute manner in mid-adolescent male rats. Cannabidiol (15 mg/kg) or vehicle were injected ip. in a single dose about 1 h prior to behavioral assessment. Three standard behavioral tests were performed: the elevated plus maze and the open field test on PND 42 and the forced swimming test on PND 43-44 on the subsequent groups of rats. The combined treatment with escitalopram and cannabidiol in ineffective doses did not induce anxiolytic-like effects but successfully relieved despair behavior in the forced swimming test showing similar efficacy as treatment with escitalopram in effective dose. This result might be the basis for future research and the development of new therapeutic strategies for treatment of adolescent depression.

The flexibility to adjust actions and attitudes in response to varying social situations is a fundamental aspect of adaptive social behavior. Adaptive social behaviors influence an individual's vulnerability to social stress. While it has been proposed that oxytocin is a facilitator of active coping behaviors during social stress, the exact mechanisms remain unknown.

Using a social defeat stress paradigm in male mice, we identified the distribution of oxytocin receptor (OXTR)-expressing neurons in the ventrolateral part of the ventromedial hypothalamus (vlVMH) that are activated during stress by detection of c-Fos protein expression. We then investigated the role of vlVMH OXTR-expressing neurons in social defeat stress responses by chemogenetic methods or deletion of local OXTRs. The social defeat posture was measured for quantification of adaptive social behavior during repeated social stress.

Social defeat stress activated OXTR-expressing neurons rather than estrogen receptor 1-expressing neurons in the rostral vlVMH. OXTR-expressing neurons in the vlVMH were glutamatergic. Chemogenetic activation of vlVMH OXTR-expressing neurons facilitated exhibition of the social defeat posture during exposure to social stress, while local OXTR deletion suppressed it. In contrast, overactivation of vlVMH-OXTR neurons induced generalized social avoidance after exposure to chronic social defeat stress. Neural circuits for the social defeat posture centered on OXTR-expressing neurons were identified by viral tracers and c-Fos mapping.

vlVMH OXTR-expressing neurons are a functionally unique population of neurons that promote active coping behavior during social stress, but their excessive and repetitive activation under chronic social stress impairs subsequent social behavior.

Male mice are frequently used for behavioral neuroscience research, but outcomes of behavioral tests are often variable across studies, contributing to poor reproducibility. Social housing conditions, social hierarchical status and within-cage order of testing are factors that likely influence behavioral outcomes, but it is unknown to what extent and if these factors interact. For this purpose, behavior of socially and individually housed male C57BL6/J mice was studied upon subjection to the open field test, the elevated plus-maze test and the three-chamber social test. In socially housed animals, effects of social hierarchical status and within-cage testing order were evaluated. We show that the differences in behavior outcomes between individually and socially housed mice depend on the social hierarchical status and the test order of the socially housed mice. Careful consideration of these factors in the design, analysis and interpretation of behavioral experiments with socially housed mice can lead to more precise results and more reliable research outcomes.

Chronic stress (Ch.S) has detrimental effects on the brain's structure and function, particularly in the hippocampus. The noradrenergic and orexinergic systems play crucial roles in the stress response and regulation of stress-related behaviors. This study aimed to investigate the interaction between noradrenergic activation and orexin receptor 1 inhibition on chronic stress-induced hippocampal alterations. The study conducted experiments on male Wistar rats, subjected to Ch.S, OXr1 blocking, noradrenergic activation, or a combination of these treatments. Plasma corticosterone level was measured using a fluorometric method. Behavioral assessment of social maze, elevated plus maze (EPM) and novel object recognition (NOR) test were performed. Then, the expression of prepro-orexin, OXr1, and glucocorticoid receptor (GR) was analyzed using semiquantitative RT-PCR. Neuronal populations were quantified through Nissl staining. The data revealed that all stress and yohimbine groups had elevated plasma corticosterone levels. Ch.S significantly altered behavior, impairing social interaction, disrupting object recognition memory and increasing anxiety-like responses in the EPM. OXr1 blocking reversed these stress-induced behavioral deficits, while yohimbine did not improve these behavioral outcomes. Chronic stress led to a significant increase in prepro-orexin, OXr1, and GR expression. While blocking OXr1 helped counteract these stress-induced changes, yohimbine failed to restore the expression levels. Ch.S reduced hippocampal neuronal populations, while OXr1 blocking partially reversed this effect, and yohimbine further recovered the reversal. These findings indicate that blocking hippocampal OXr1 can mitigate the adverse effects of chronic stress on both hippocampal structure and anxiety-like behaviors, while noradrenergic signaling appears to have differential effects on behavioral and cellular measures.

Post-traumatic epilepsy (PTE) is a common, serious, long-term complication of traumatic brain injury (TBI). However, only a minority of individuals will develop epilepsy after a TBI, and the contribution of genetic predisposition to the risk of acquired epilepsy warrants further exploration. In this study, we examined whether innate, genetically determined differences in seizure susceptibility between seizure-prone FAST and seizure-resistant SLOW rat strains would influence chronic behavioral and PTE outcomes after experimental TBI. We hypothesized that FAST rats would show increased vulnerability to PTE and poorer neurobehavioral outcomes. Using the lateral fluid percussion injury model, we first determined the optimal injury parameters to generate a mild-moderate TBI in young adult FAST rats, which had previously shown high mortality to severe TBI. Then, FAST and SLOW rats underwent TBI or sham surgery, and a series of behavioral tests were performed either acutely (within 4 weeks) or chronically (more than 22 weeks) post-injury. Acutely, FAST rats showed an increased physiological response to TBI with a longer apnea duration, delayed pain response, and delayed self-righting, as well as increased acute seizure-like behavior compared to SLOW rats. Conversely, SLOW rats showed greater neuromotor deficits and weight loss sub-acutely compared to FAST rats. Chronically, while strain-specific phenotypes were observed (e.g., FAST rats showing increased anxiety-like behavior, altered nociceptive responses, and polydipsia), no TBI effects were detected. Analysis of continuous video-electroencephalographic recordings over a 1-month period starting at 6 months post-TBI did not reveal any spontaneous seizures. However, periodic epileptiform discharges were only found in FAST rats that had a TBI. Together, these findings reflect fundamental differences in chronic behavior and epileptiform discharges as a result of innate distinctions in epileptogenic susceptibility in FAST versus SLOW rats. However, a lack of spontaneous seizure activity or chronic neurobehavioral deficits in TBI animals confounded our ability to address the initial hypothesis, such that alternative injury models may be more suitable to study genetic contributions to the development of PTE.

Environmental enrichment and social isolation constitute two well-studied experimental manipulations that result in several behavioral, neural, and molecular changes in rodents. Enrichment is linked to enhanced cognitive performance, and mitigation of different nervous system injuries and disorders. In contrast, social isolation or impoverished environment often induce negative effects on cognitive and affective systems. Both manipulations are typically examined with a short-term or chronic exposure, which cannot capture the actual human experiences. In this study, we explored the behavioral and neural alterations led by intermittent environmental enrichment or social isolation in adult Wistar rats. Animals were assigned to an enriched condition (EC), isolation/impoverished condition (IC), or standard condition (SC). The differential housing protocol involved transferring the animals to their respective cages for two days at the end of each five-day standard housing period for 8 weeks. Enriched animals exhibited behavioral despair in the forced swim test without differential overall locomotor activity. In the Morris water maze, impoverished animals displayed a slower learning rate compared to the SC and EC groups. In line with this, the IC group had fewer parvalbumin (PV) immunopositive (+) cells in the CA1 and dentate gyrus. No differences were observed in PV+ cell levels in the amygdala, while the IC group had more c-Fos+ cells in the same region following acute restraint stress. These findings implicate that intermittent isolation or enrichment are sufficient to trigger distinct behavioral changes at the cognitive and affective domains, and pinpoint PV as a biomarker for environmentally induced alterations in hippocampal memory performance.

Exposure to traumatic events can lead to alterations in social and anxiety-related behaviors. Emerging evidence suggests that peripheral host-defense processes are implicated in the expression of stress-induced behavioral responses and may be targeted to mitigate the negative sequalae of stress exposure.

In this study, we used the peripherally restricted FAAH inhibitor URB937 to investigate the effects of the fatty acyl ethanolamide (FAE) family of lipid mediators - which include the endocannabinoid anandamide and the endogenous PPAR-α agonists, oleoylethanolamide and palmitoylethanolamide - on behavioral and peripheral biochemical responses to two ethologically distinct rat models of stress.

Male adult rats were exposed to acute social defeat, a model of psychological stress (Experiment 1), or to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT), a test of innate predator-evoked fear (Experiment 2), and subsequently treated with URB937 (1 or 3 mg/kg, intraperitoneal) or vehicle. Behavioral analyses were conducted 24 h (Experiment 1) or 7 days (Experiment 2) after exposure.

URB937 administration prevented the emergence of both social avoidance behavior after social defeat stress and anxiety-related behaviors after TMT exposure. Further, URB937 administration blocked social defeat-induced transient increase in plasma concentrations of pro-inflammatory cytokines and the elevation in plasma corticosterone levels observed 24 h after social defeat CONCLUSIONS: Enhancement of peripheral FAAH-regulated lipid signaling prevents the emergence of stress-induced social avoidance and anxiety-like behaviors in male rats through mechanisms that may involve an attenuation of peripheral cytokine release induced by stress exposure.

GPR171 is a recently deorphanized G protein-coupled receptor that has been implicated in feeding, mood regulation, and pain. However, the role of this receptor in other physiological functions and in female mice is largely unexplored. Using a novel genetic GPR171 knockout mouse model, we examined general physiological behaviors and mood-related behaviors in both sexes. In male GPR171 knockout mice, we observed increased feeding, reduced water intake, heightened ataxia, and decreased anxiety-like behaviors. Male GPR171 knockout mice showed greater depressive-like behaviors compared to female knockout mice, but this did not correspond to a change in cFos activity in the basolateral amygdala. No significant changes were detected in female GPR171 knockout mice in other behaviors measured. These findings corroborate previous studies linking GPR171 to feeding and mood regulation in males, but highlight notable sex differences that were previously unknown. These sex differences indicate that future studies should focus on elucidating the behavioral effects of GPR171 in females to provide a more comprehensive understanding of its physiological roles.

Anxiety, a future-oriented negative emotional state, is characterized by heightened arousal and vigilance. The elevated plus maze (EPM) test is a widely used assay of anxiety-related behaviors in rodents and shows a phenomenon where animals with prior test experience tend to avoid open arms in retest sessions. While this one-trial tolerance (OTT) phenomenon limits the reuse of the EPM test, the potential mechanisms remain unsolved. Here, we found that neither anxiogenic factors like acute restraint stress nor anxiolytic factors like diazepam (2 mg/kg) influenced the emergence of the OTT phenomenon in mice in the EPM test. In contrast, OTT was markedly attenuated by MK-801 (0.1 mg/kg), a non-competitive N-methyl-D-aspartate receptor antagonist. Through the use of c-fos mapping, MK-801 was found to increase neuronal activation in the thalamic nucleus reuniens (Re). Moreover, chemogenetic inactivation of Re neurons could prevent the effects of MK-801. Our findings suggest the Re as a crucial brain region in emotional adaptation in the EPM and shed light on the experimental design optimization and mechanistic investigation of anxiety-related behaviors.

To evaluate the behavioural effects in adult mice previously subjected to audiovisual overstimulation during infancy and adolescence.

Mice aged 21, 26 and 36 days (p21, p26 and p36) underwent auditory (70 db) and visual (flashing lights) stimulation for 2 or 6 h per day until p64; naive animals were used as controls. At p200, tests assessed respectively motor activity (open field test), depression (forced swimming and splash tests), anxiety (hole board, plus maze and marble burying tests, aggression (resident-intruder test), and nociception (von Frey and hot plate tests).

There were no significant (ANOVA, p > 0.05) behavioural changes in forced swimming, splash, hole board, or marble burying tests between overstimulated and naive groups. However, the p21 group showed significantly (ANOVA, p < 0.05) increased anxiety-like behaviour (2 h) in the elevated plus maze test and altered nociceptive behaviour in the von Frey test (2 and 6 h). The p26 group (2 h) displayed significantly reduced rearing behaviours, fewer entries in the plus maze test, and faster reaction times to noxious thermal stimulation (2 h).

Audiovisual overstimulation during early development can promote anxiety-like behaviour and affect nociceptive behaviour in adult mice.

Millions of people take hormonal contraceptives (HCs), often starting during adolescence when ovarian hormones influence brain and behavioral maturation. However, there is a fundamental lack of information about the neurobehavioral consequences of hormonal alterations via adolescent HC use. To begin addressing this gap, we validated a rodent model of adolescent HC administration and characterized its impact on endocrine, transcriptional, and behavioral endpoints. Cohorts of intact post-pubertal female Sprague-Dawley rats received daily subcutaneous injections of either vehicle or HC [10 μg ethinyl estradiol (EE) + 20 μg levonorgestrel (LNG)] for the duration of adolescence from postnatal day (PND) 35 to PND56. Blood and brain tissue was collected at PND57. Other cohorts received daily injections of vehicle or HC from PND35 until behavioral assays were completed on PND57-64. HC treatment was effective, as vaginal lavage indicated disrupted estrous cycling and ELISA indicated suppressed serum luteinizing hormone in HC-treated rats. Liquid chromatography-mass spectrometry analysis showed EE and LNG in serum and brain as well as diminished serum and brain levels of allopregnanolone and testosterone in HC-treated rats. NanoString nCounter analysis indicated that adolescent HC administration impacted expression of genes related to synapses, white matter, neuroimmune, monoamine, and hormone signaling in the hypothalamus and medial prefrontal cortex. While no effects of HCs were seen on sociability in the social preference test or stress coping behavior in the forced swim test, adolescent HC administration diminished risk-assessment behaviors in the novelty-induced hypophagia paradigm and altered anxiety-like behavior in the open field test and elevated plus maze. Overall, these data suggest that exposure to contraceptive hormones during the critical developmental period of adolescence may shape the brain and behavior.

Although chronic psychosocial stress is linked to cardiovascular diseases, the underlying mechanisms remain elusive. For this study, we focused on the mitochondrion as a putative mediator of stress-related cardiac pathologies in a sex-dependent manner. Male and female Wistar rats were subjected to chronic stress for 4 weeks (mimicking an anxious phenotype) versus matched controls. Cardiac redox status, mitochondrial respiration parameters, and expression levels of proteins involved in mitochondrial oxidative phosphorylation, dynamics, and biogenesis were evaluated. Despite limited changes in behavior and circulating stress hormones (both sexes), stressed males exhibited altered cardiac oxidative phosphorylation via β-oxidation- and glucose oxidation-linked respiratory pathways together with increased myocardial antioxidant capacity and decreased lipid peroxidation. Conversely, stressed females exhibited a protective and resilient phenotype by displaying augmented levels of major mitochondrial respiratory complexes (complex I, III, and ATP synthase) and a fusion marker (mitofusin-2 [Mfn2]), together with attenuated expression of a fission marker (dynamin-related protein-1 [Drp1]) despite decreased estradiol levels. In contrast, stressed males displayed increased cardiac ATP synthase levels together with diminished peroxisome proliferator-activated receptor-gamma coactivator-1-alpha (PGC-1α) expression versus controls. These findings indicate that male mitochondria are more prone to stress-related functional changes, while females exhibited a more protective and resilient phenotype.

Telomeres are increasingly recognized for their potential role in the etiology of autism spectrum disorder (ASD) due to their involvement in cellular aging and telomerase-shelterin function. Although shorter telomeres have been observed in individuals with ASD, studies linking telomere dynamics in blood cells and brain regions remain limited. Using the valproic acid (VPA, 500 mg/kg) rodent model, this study aimed to assess the impact of three drugs commonly used in ASD treatment (amitriptyline, risperidone, and nooclerin) on telomere length and the expression of telomerase/shelterin-related genes (Dkc1, Gar1, Pot1a, Pot1b, Tep1, Terc, Terf2ip, Tert, Tinf2, Tnks, Tpp1, Trf1, and Trf2) in blood cells, the prefrontal cortex, and hippocampus of VPA-exposed Wistar rats. Telomere length and gene expression were measured using quantitative PCR. Risperidone treatment in VPA males resulted in telomere elongation and increased expression of Tnks in blood cell and Trf1, Trf2 genes in prefrontal cortex. Nooclerin treatment also showed beneficial effects on telomere length of blood cell in males, alongside increased Trf1 expression. Long telomeres in male blood cells were associated with reduced anxiety, while a positive correlation was found between Tpp1 expression and stereotypical behavior in both male and female VPA rats. These findings suggest that nooclerin and risperidone influence telomere length and gene expression related to the telomere-telomerase complex in a sex-dependent manner, offering insights into the neurobiological mechanisms underlying ASD.

Rationale: The COVID-19 pandemic, driven by SARS-CoV-2, has resulted in a wide range of neuropsychiatric symptoms associated with post-acute sequelae (PASC). However, the mechanisms by which SARS-CoV-2 impacts the brain and leads to persistent behavioral changes remain poorly understood. We hypothesize that SARS-CoV-2 exposure induces neuroinflammation and microglial activation, leading to anxiety- and depression-like behaviors in mice. Methods: We established a SARS-CoV-2 mouse model using the virulent SARS2-N501YMA30 strain to investigate its impact on the central nervous system (CNS). We assessed neuroinvasion via immunostaining of dsRNA and markers for neuronal, astrocyte, and microglia in brain slices. Behavioral changes were evaluated at 2 weeks, 2 months, and 4 months post-infection. Molecular and cellular analyses included bulk RNA-seq, Golgi-Cox staining, field excitatory postsynaptic potential (fEPSP) recordings, immunofluorescence, and quantitative real-time PCR (qRT-PCR) to assess gene expression, neuronal morphology, and microglial activation in the brain. Results: We demonstrated that intranasal inoculation of SARS2-N501YMA30 results in viral dissemination to multiple brain regions, including the amygdala and the prefrontal cortex (PFC). Behavioral assays indicated a marked elevation in anxiety- and depression-like behaviors post-infection. A comparative analysis of RNA expression profiles disclosed alterations in the post-infected brains. Additionally, we observed dendritic spine remodeling on neurons within the amygdala after infection. Infection with SARS2-N501YMA30 was associated with microglial activation and a subsequent increase in microglia-dependent neuronal activity in the amygdala. Transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Conclusion: Our findings provide evidence that SARS-CoV-2 neuroinvasion plays a critical role in the development of lasting behavioral sequelae observed in PASC. These data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.

Radiation-induced cognitive impairment (RICI) and emotional disorder (RIED) are comorbidities that seriously affect the quality of life in patients with radiation-induced brain injury (RIBI). A longitudinal study was conducted to observe the occurrence and development of RICI and RIED in an RIBI animal model and a clinical cohort following intensity modulated radiotherapy (IMRT). RIBI mice and sham controls were subjected to three cycles of behavior tests for cognitive and emotional function at post-irradiation 1 week (1w), 5 weeks (5w), and 9 weeks (9w) corresponding to early, middle and late stage after radiotherapy. Additionally, 139 patients who underwent IMRT after nasopharyngeal carcinoma and were firstly diagnosed with radiation-induced brain injury were enrolled. Pre-treatment and follow-up neuropsychological assessments of cognition, anxiety and depression were completed. Compared with control, significant declines in working memory, object recognition memory and social memory were observed in RIBI mice at post-irradiation 5w and 9w. Longitudinal observations revealed that memory impairment predominantly occurred in the middle stage and persisted into the late stage. Anxiety-like behaviors were only observed at post-irradiation 9w. In the clinical cohort, RICI exhibited a parallel cumulative incidence curve and a similar median onset to RIBI. RICI predominantly occurred 2-6 years post-IMRT 2-6 and progressively deteriorated beyond 6 years while RIED gradually increased beyond 6 years after IMRT. During two-year follow-up visits, half of the patients with RICI combined with RIBI benefited from drug treatment, achieving stable or improved cognition, while the other half showed no response or experienced cognition aggravation. In summary, RICI predominantly occurred in the middle stage post-irradiation and progressed to the late stage while RIED mostly emerged in the late stage in RIBI. Consistency in the development process of RICI and RIED was observed in the animal model and the clinical cohort.

The aim of our study was to analyze the impact of early-life overnutrition and the exposure in adulthood to a cafeteria diet (CAF) on eating behavior and on the expression of key genes involved in the regulation of food intake. Male Wistar rats were raised in small (SL, 4 pups/dam) or normal litters (NL, 10 pups/dam), fed a control diet (CON) until postnatal day (PND) 90. Then, they received CON or CAF for 11 weeks (NL-CON, NL-CAF, SL-CON, SL-CAF; 12±2 rats/group). Body weight, food intake and behavioral tests (Elevated Plus Maze: EPM, Sensory-specific satiety: SSS) were assessed. At PND167, the rats were euthanized to obtain brain, blood and fat pads. Ventral tegmental area (VTA), Nucleus Accumbens (NAc) and Arcuate Nucleus (Arc), were isolated by micropunch technique for qPCR analysis. Early overfeeding alone had the ability to alter long-term SSS. CAF groups showed increased body weight, adiposity and energy intake; sweet food preference and altered SSS. SL-CAF showed hypophagia, basal hyperglycemia, altered SSS and anxiety-like behavior. Both NL-CAF and SL-CAF showed antidopaminergic effects, but through different pathways: NL-CAF reduced dopamine (DA) production in VTA via decreased tyrosine hydroxylase (TH) expression, while SL-CAF exhibited an increase in dopamine active transporter (DAT) expression in NAc enhancing clearance. SL decreased Neuropeptide Y (NPY) expression in the Arc in adulthood, which has been proposed to be the link between homeostatic and hedonic systems. Our research reveals a key link between early-life overnutrition and adult hedonic feeding control, emphasizing its lasting impact on eating behavior and the potential for innovative therapeutics to combat obesity.

Type 2 diabetes (T2D) is a metabolic disorder commonly linked with cognitive decline, increasing patients' susceptibility to dementia. Alzheimer's disease (AD) has a strong connection with hyperglycemia and insulin dysregulation. Interestingly, certain anti-diabetic drugs have shown potential in reducing T2D-induced cognitive impairment. Previous studies, including ours, have highlighted the dysregulation of cyclin-dependent kinase 5 (Cdk5) activity in both T2D and AD, which may contribute to pathological changes in these conditions. Thus, targeting the Cdk5 kinase could offer a therapeutic approach for T2D and cognitive deterioration. Our research identifies Cdk5 as a key link between T2D and cognitive decline. By screening the KINACore library, we discovered two new brain-penetrant Cdk5 inhibitors, BLINK11 and BLINK15. In a high-fat diet-induced T2D model, these inhibitors improved blood glucose levels, obesity, and cognitive function. BLINK11, in particular, shows promise as a therapeutic candidate for treating cognitive impairment associated with T2D.

Research has indicated a strong link between exposure to aluminum (Al) and the development of Alzheimer's disease (AD). Given the rising use of Al nanoparticles, which are far more neurotoxic than Al, it is noteworthy to investigate the possible protective properties of natural substances. Curcumin, an important component of turmeric, has demonstrated neuroprotective effects in some animal studies. The main objective of this study was to examine the protective effects of curcumin on the memory deficit induced by subcutaneous aluminum oxide nanoparticles (Al-NP) administration in mice. Additionally, considering the roles of the hippocampal brain-derived neurotrophic factor (BDNF) and Akt pathway in AD pathology, their levels were evaluated. Adult male Swiss mice (SWR/J) were administered Al-NP (10 mg/kg/s.c.) with or without curcumin (2.5, or 25 mg/kg/P.O) for 10 days. Memory and anxiety-like behavior were assessed using passive avoidance and elevated plus maze tasks, respectively. Western blot analysis was employed to measure hippocampal BDNF and Akt proteins in the hippocampus. The findings revealed that Al-NP induced memory impairment in mice, whereas curcumin at 25 mg/kg prevented this memory deficit. Additionally, Al-NP significantly reduced the hippocampal BDNF and phosphorylated Akt levels, while curcumin increased BDNF and phosphorylated Akt to a nonsignificant level compared to the control group. These results not only suggest the neuroprotective properties of curcumin but also suggest a possible association between hippocampal BDNF and Akt signaling in the neuroprotective mechanism of this compound against Al-NP toxicity.

Cortical layer 6 neurons are the only projection neuron population in the cortical mantle known to electrophysiologically respond to orexin-a neuropeptide involved in cortical arousal and emotive behaviour. These neurons exhibit extensive intercortical and thalamic projections, yet the exact mechanisms underlying these responses are not fully understood. We hypothesize that cortical circuits activated by orexin sensitive L6 neurons in the medial prefrontal cortex (mPFC) are responsible for detecting salient features of sensory stimuli and are therefore involved in regulating emotional states. Here, we show that Drd1a-Cre+ neurons in the mPFC are selectively sensitive to orexin and gate the activation of the prefrontal network in vivo. Moreover, we demonstrated that chronically "silencing" this subpopulation of L6 neurons (Drd1a-Cre+/+:Snap25fl/fl) across the cortical mantle from birth abolishes the orexin-induced prefrontal activation. Consequently, the chronic silencing of these neurons had strong anxiolytic effects on several anxiety-related behavioural paradigms, indicating that orexin-responsive L6 neurons modulate emotional states and may be a substrate for anxiety regulation.