Cognitive deficits are a major contributor to disability in numerous neuropsychiatric and neurodegenerative disorders, yet effective pharmacological treatments remain limited. Ferulic acid eicosyl ester (FAE-20), a natural constituent of the plant Rhodiola rosea, has previously been identified as an enhancer of simple forms of Pavlovian conditioning in flies, bees, and mice. Here, we investigated whether FAE-20 has further potential to enhance cognitive flexibility, working memory, or spatial learning in mice, and explored potential neurobiological mechanisms underlying such enhancement. Cognitive flexibility was assessed using the attentional set-shifting task (ASST). Subchronic FAE-20 treatment significantly improved ASST performance in both male and female young adult mice, indicating enhanced cognitive flexibility. In contrast, no effects were observed on spatial working memory, assessed by spontaneous alternations in the Y-maze, or on spatial learning in the Barnes maze in either young or aged mice. Notably, FAE-20 enabled spatial learning in the Barnes maze in a subgroup of aged mice that failed to learn the task under vehicle treatment. Histological analyses using c-Fos immunohistochemistry as a marker of neural activity and doublecortin expression and spine density as markers of hippocampal plasticity revealed sex-specific effects on components of the ascending arousal system. FAE-20 increased the activation of orexinergic neurons in the lateral hypothalamus of male mice, whereas it reduced the activity of cholinergic neurons in the laterodorsal tegmental nucleus of females. No effects were detected on hippocampal neurogenesis or dendritic spine density. These findings suggest that the cognitive effects of FAE-20 are selective, depending on the cognitive demands of the task and the baseline cognitive abilities of the animals, and may be mediated, at least in part, by modulation of arousal-related neural circuits.

Cerebral ischemia-reperfusion (I/R) injury induces neuronal death via caspase-dependent apoptosis and parthanatos, a poly (ADP-ribose) polymerase 1 (PARP-1)/apoptosis-inducing factor (AIF)-mediated caspase-independent pathway. Simultaneous inhibition of these pathways may provide enhanced neuroprotection. N-Stearoyltyrosine (NsTyr), a synthetic analogue of the endocannabinoid anandamide (AEA), exhibits neuroprotective effects in various models, however, its efficacy and mechanism in middle cerebral artery occlusion (MCAO) remain unclear. Neuronal oxygen-glucose deprivation/ reoxygenation (OGD/R) and rat MCAO models were employed to evaluate the neuroprotection of NsTyr. Neuronal viability and apoptosis were assessed using MTT assay, flow cytometry, TUNEL staining, and Hoechst 33342 staining. The cognitive impairment was evaluated using the Morris water maze. Mitochondrial function and ultrastructure were eassessed by JC-1 assay and transmission electron microscopy (TEM). Expression levels of key apoptotic-related proteins were determined by immunoblotting. Intracellular NAD[+] and ATP levels were measured to assess PARP-1 activity. NsTyr significantly improved neuronal survival, reduced apoptosis, and ameliorated cognitive deficits in both in vitro and in vivo models. Mechanistically, NsTyr preserved mitochondrial integrity, maintained the Bcl-2/Bax balance, suppressed cytochrome c release and caspase-3 activation, and inhibited nuclear translocation of AIF. Concurrently, NsTyr attenuated PARP-1 overactivation, preserved NAD[+] and ATP levels, and thereby suppressed parthanatos. These findings demonstrate that NsTyr confers potent neuroprotection against I/R injury by dual inhibition of caspase-dependent apoptosis and PARP-1/AIF-mediated parthanatos through the maintenance of mitochondrial integrity, supporting its potential as a therapeutic candidate for ischemic stroke.

Freediving in rats has emerged as a relevant model to study physiology and neural adaptation underlying submersion mechanisms. However, despite well-established strain-dependent differences in behavior and physiological responses, most studies about freediving rely on Sprague Dawley rats. As the choice of strain could significantly shape experimental results depending on the field of research, we conducted a behavioral comparative study between Long Evans (LE) rats, genetically closer to the Wild Norway rat, with the commonly used Sprague Dawley (SD) strain. We developed an 11-week progressive voluntary freediving protocol involving four distances (from 5 to 11 meters), and assessed the rats' natural willingness to dive and swim, and identified several parameters for evaluation of their confidence (waiting time before diving, speed), performance capacity (freediving time) and population variability. We found that Long Evans rats were naturally more willing to dive and more confident, compared to Sprague Dawley rats: they showed better performance with longer time underwater and slower diving speed. We also uncover differences in their variability, at trial-to-trial intra-individual and population inter-individual levels, which can guide the choice of one strain over the other, depending on the aim of the scientific inquiry.

Early-life stress (ELS), i.e., traumatic events during vulnerable developmental periods, adversely affects adult psychobiological outcomes, with dysregulated noradrenergic processing of trauma proposed to play a role. Guanfacine, a selective alpha-2A adrenergic receptor agonist that blunts noradrenergic signalling in mammals by activating the alpha-2A inhibitory autoreceptor, may be useful to attenuate the long-term consequences of ELS. The zebrafish (Danio rerio) is extensively used in stress research. Here, we investigated the immediate and long-term effects of a traumatic ELS procedure combined with control or guanfacine (20µg/L) treatment in 264 juvenile zebrafish. Immediate assessments in 168 juveniles included anxiety-like and risk-taking behaviours using the light-dark test (LDT) and open field test (OFT). Long-term assessments in 96 fish raised to adulthood included anxiety-like behaviour using the novel tank test (NTT) and open field avoidance and aggressor-directed risk-taking behaviour in a novel OFT (nOFT). We found that traumatic stress exposure only modestly impacted the immediate anxiety-like behaviours of juvenile zebrafish, while guanfacine had distinct stress-dependent effects on behaviour. Guanfacine elicited anxiety-like behaviours under conditions of novelty (i.e., testing in the absence of a prior traumatic experience), but had the opposite effect and suppressed anxiety-like behaviours in trauma-exposed fish. Our results also showed that zebrafish exhibit a high degree of resilience to the long-term impact of traumatic stress, as neither traumatic stress exposure, nor guanfacine administration, affected anxiety-like or risk-taking behaviours in adulthood. These findings illustrate the presence of evolutionary conserved adaptive neurobiological mechanisms in zebrafish that may blunt the impact of traumatic events.

Individuals with depression often engage in iterative "rumination" about challenging situations and potential outcomes. Although the state of rumination has been associated with diverse univariate neurophysiological features, the potential to use multivariate patterns to decode it remains uncertain. In this proof-of-principle study, we trained participant-specific linear support vector machines to differentiate state rumination from distraction using patterns in the alpha, beta, and theta bands, as well as inter-channel connectivity. We used validated tasks to induce rumination or distraction for eight minutes in 24 depressed individuals in six runs over three sessions. During inductions, we recorded 64-channel EEG data and measured self-reported levels of rumination. Participants reported strongly increased rumination, and averaged across all participant-specific decoders we classified state rumination from EEG patterns with small albeit significant accuracy. However, on an individual level, decoding reached accuracies above chance level in only 10 out of 24 participants with heterogenous feature weights across individuals. Our study demonstrates that ruminative states can be decoded from inter-individually heterogenous neurophysiological patterns, but variability in ruminative processes limits the generalization of decoding approaches across participants.

The prefrontal cortex (PFC) plays a critical role in decision-making under uncertainty. Although prior studies have shown that PFC subregions influence risky choice in tasks manipulating reward probability, their contributions to decision-making across different levels of risk, independent of expected value, remain unclear. In the present study, we examined the effects of excitotoxic lesions of the lateral orbitofrontal cortex (lOFC) and the medial PFC (mPFC) on a novel T-maze risk choice task in male rats. In this task, expected value was held constant across choice options, while outcome variance was manipulated using three reward ratios corresponding to low, medium, and high levels of risk. Control rats developed distinct choice patterns across risk levels, exhibiting risk-prone behavior under low risk and risk-averse behavior under high risk. The acquisition of risk-dependent choice was differentially modulated by lOFC and mPFC lesions, with more pronounced effects of lOFC lesions under the low-risk condition. Microstructural analysis revealed that lOFC lesions altered sensitivity to negative feedback, as reflected by decreased lose-stay and increased lose-shift responses. Computational modeling further indicated that lOFC function was associated with reward learning and choice persistence, whereas mPFC function was related to learning from both reward and punishment outcomes. Together, these results demonstrate dissociable roles of the lOFC and mPFC in risk-dependent decision-making. Specifically, the lOFC plays a critical role in stabilizing choice behavior under low-risk conditions, likely by modulating choice persistence in response to negative feedback, a function that may contribute to the processing of outcome variability during risk-dependent choice.

Systemic inflammation triggers a coordinated sickness response that includes behavioral suppression, anorexia, and thermoregulatory alterations, often viewed as a unified syndrome. However, increasing evidence suggests that distinct neural circuits govern different components of sickness behavior. Whether central endocannabinoid system (ECS) signaling differentially regulates behavioral and thermoregulatory responses during systemic inflammation remains unclear. We therefore investigated the role of central ECS signaling in specific sickness domains induced by lipopolysaccharide (LPS). Male Wistar rats received intracerebroventricular pretreatment with the CB1 receptor antagonist AM251, the endocannabinoid transport inhibitor VDM11, the CB1 agonist WIN55,212-2, or vehicle prior to intraperitoneal administration of LPS (1 mg/kg) or saline. Behavioral responses were assessed using the open field test, forced-swim test, and 24-h food intake. Core body temperature was continuously monitored by telemetry for 6 h, and thermal indices were calculated for hypothermia (0-2 h) and fever (3-6 h). LPS induced a robust sickness phenotype characterized by reduced locomotion, increased immobility, hypophagia, and a biphasic thermoregulatory response. Central ECS manipulations produced minimal effects on behavioral endpoints. In contrast, thermoregulation was selectively sensitive to ECS modulation: CB1 receptor blockade enhanced LPS-induced hypothermia and markedly reduced fever, whereas increasing endocannabinoid tone attenuated hypothermia without affecting fever. These findings demonstrate that central ECS signaling selectively modulates thermoregulatory, but not behavioral, components of the sickness response, supporting a modular organization of sickness behavior.

Neuropeptide Y (NPY) exerts neuroprotective effects; however, its functional relationship with autophagy-related signaling pathways in AD-associated cognitive dysfunction remains insufficiently understood. Using an Aβ-induced rat model of AD, the present study evaluated the effects of NPY on learning and memory. Specifically, we examined whether pharmacological manipulation with 3-methyladenine and MHY1485 modifies the cognitive effects of NPY, providing an indirect behavioral-pharmacological assessment of processes potentially related to autophagy and mTOR signaling.

During recent years, researchers have extensively investigated various health issues associated with prenatal challenges and the subsequent outcomes emerging in the next generation. In this respect, prenatal exposure to infections is correlated with the development of cognitive deficits in offspring. There is evidence indicating that disturbance of maternal microbiota adversely affects the gut-brain axis, which in turn could compromise fetal development and cause persistent physiological defects. Previous studies have reported that Helicobacter pylori infection is correlated with cognitive decline; however, this issue has not been investigated in offspring. Therefore, we applied behavioral methods to reveal how maternal H. pylori infection could affect memory function using the Morris water maze and novel object recognition in male offspring. Then, the cellular mechanisms associated with H. pylori-induced effects were probed using specific biochemical measurements in hippocampal tissues. Results indicated that spatial and recognition memory is impaired in offspring born from mothers with a history of H. pylori infection, and this appears to be correlated with a disturbance of the balance among oxidative, inflammatory, serotonergic, and cholinergic profiles within the hippocampi. In addition, the mentioned H. pylori-related effects were found to be biochemically restored and behaviorally ameliorated by pharmacological inhibition of the monoamine oxidase enzyme, proposing a potential for amelioration of cognitive outcomes.

Obsessive-compulsive disorder (OCD) is a debilitating condition associated with repetitive behaviors and cognitive inflexibility, often linked to abnormalities in cortico-striato-thalamo cortical (CSTC) circuitry. Although the Slitrk5 knockout (Slitrk5[-/-], KO) mouse has been proposed as an OCD-related model, it remains unclear how Slitrk5 deficiency influences adaptive decision making, task-related behavioral organization, and orbitofrontal-dorsomedial striatum (OFC-DMS) signaling during reversal learning. To address this, Slitrk5[-/-] and wild-type (WT) mice were examined using probabilistic reversal-learning paradigms combined with licking-behavior analyses, fiber photometry recordings, optogenetic inhibition of OFC-DMS projections, and open-field assessment. Across paradigms, Slitrk5[-/-] mice displayed largely preserved reversal-learning performance and adapted to changing reward contingencies similarly to WT mice. However, genotype-dependent differences emerged in how licking behavior was organized across behavioral epochs and reward contingencies, indicating altered anticipatory, choice-related, and reward-associated responding during task performance. Fiber photometry recordings further identified altered OFC-striatal signaling in Slitrk5[-/-] mice across anticipatory and reward-associated behavioral periods. In contrast, optogenetic inhibition of OFC-DMS projections produced no detectable effects on reversal-learning performance or licking behavior. Open-field assessment revealed age-dependent alterations in locomotor and exploratory behavior together with progressive grooming-related lesion development. Together, these findings demonstrate selective alterations in task-related behavioral organization and OFC-striatal signaling despite preserved reversal-learning performance in Slitrk5[-/-] mice, highlighting the heterogeneous behavioral and neural expression associated with corticostriatal dysfunction across OCD-related phenotypes.

The tumor suppressor protein p53 is a known modulator of neurodegenerative disease (ND) processes. Although p53 expression is increased in the brains of patients with Alzheimer's disease, Parkinson's disease, and ischemic stroke, its role in mood disorders such as anxiety and depression remains unclear. To investigate the role of p53 in behavioral responses to chronic stress, we examined behavioral and molecular alterations in p53 knockout (p53[-/-]) mice and wild type mice. In p53[-/-] mice, increased vulnerability to chronic unpredictable mild stress (CUMS)-induced anxiety- and depression-like behaviors was observed following CUMS exposure. In parallel with these behavioral changes, BDNF expression was reduced, whereas glutamate levels were elevated in the prefrontal cortex of p53[-/-] mice. Increased calcium-associated staining and NMDAR2B expression were observed together with increased neuronal injury- and cell death-related markers. In primary cortical neurons derived from p53[-/-] mice, corticosterone treatment resulted in greater increases in glutamate levels, NMDAR2B expression compared to wild-type controls. Cell death markers (cleaved caspase-3, p-p38, p-JNK) were upregulated, while neuroprotective signals (BDNF, p-Akt, p-ERK, p-CREB) were suppressed in p53[-/-] mice, and corticosterone-treated primary neuronal cells from p53[-/-] mice. These findings indicate that p53 deficiency is associated with enhanced vulnerability to CUMS-induced anxiety- and depression-like behaviors and is accompanied by alterations in calcium handling, glutamate homeostasis, neuronal injury-related markers, and BDNF-associated neuroprotective signaling.

Risperidone is an atypical antipsychotic that exerts widespread effects on cognitive functioning. Antipsychotics are most often administered to individuals with schizophrenia, providing relief from positive symptoms primarily through antagonism of the D2 dopamine receptor. One behavior that is often abnormal in schizophrenia and is partially mediated by the D2 receptor is risky decision-making. Therefore, it is critical to understand how antipsychotics impact risky decision-making in healthy subjects to disentangle the influence of schizophrenia and antipsychotics. Here, the effects of risperidone were examined in rats trained in the Risky Decision-making Task (RDT), in which subjects choose between a small, safe reward and a large reward accompanied by escalating risk of mild footshock. Both daily and acute administration of low to medium doses of risperidone induced a female- specific decrease in choice of options associated that had previously been associated with risk, even when the risk was not present. High-dose risperidone reduced risky choice in both sexes, which likely reflected risk aversion in males and cognitive or motivational disruption in females. Moreover, daily risperidone caused a stark reduction in total trials completed and weight in female but not male rats. Shock threshold testing revealed that risperidone-driven avoidance of risky options was unrelated to altered shock sensitivity, but reduced responding on a progressive ratio schedule suggested that risperidone may reduce risky choice by attenuating appetitive motivation. These findings align with emerging evidence of increased sensitivity to cognitive effects of antipsychotics in females.