The cycle of stress: A systematic review of the impact of chronic psychological stress models on the rodent estrous cycle.

Stress is known to impair reproduction through interactions between the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-gonadal (HPG) axes. However, while it is well accepted that stress can alter estrous cycle regularity, a key indicator of female's HPG axis function, effects of different types of psychological stress have been inconsistent. This systematic review evaluated the impact of rodent models of psychological stress on estrous cyclicity, while reporting biological parameters pertaining to HPA or HPG axis function assessed within these studies. We performed a systematic database search and included articles that implemented a psychological stress model in rodents and reported estrous cyclicity for at least two cycles after initiation of stress. Of the 32 studies included, 62.5% reported post-stress alterations to estrous cyclicity, with Chronic Mild Stress (CMS) models showing the most conclusive effects. Twenty-five studies measured HPG or HPA axis markers, with cycle disruptions being commonly observed in parallel with altered estradiol and increased corticosterone levels. Our review highlights gaps in reporting estrous cyclicity assessments and makes recommendations to improve comparability between studies.

Global cerebral ischemia in adult female rats interrupts estrous cyclicity and induces lasting changes in hypothalamic-pituitary-gonadal axis signaling peptides.

Persistent post-ischemic alterations to the hypothalamic-pituitary-adrenal (HPA) axis occur following global cerebral ischemia (GCI) in rodents. However, similar effects on hypothalamic-pituitary-gonadal (HPG) axis activation remain to be determined. Therefore, this study evaluated the effects of GCI in adult female rats (via four-vessel occlusion) on the regularity of the estrous cycle for 24-days post ischemia. A second objective aimed to assess persistent alterations of HPG axis activation through determination of the expression of estrogen receptor alpha (ERα), kisspeptin (Kiss1), and gonadotropin-inhibitory hormone (GnIH/RFamide-related peptide; RFRP3) in the medial preoptic area (POA), arcuate nucleus (ARC), dorsomedial nucleus (DMH) of the hypothalamus, and CA1 of the hippocampus 25 days post ischemia. Expression of glucocorticoid receptors (GR) in the paraventricular nucleus of the hypothalamus (PVN) and CA1 served as a proxy of altered HPA axis activation. Our findings demonstrated interruption of the estrous cycle in 87.5 % of ischemic rats, marked by persistent diestrus, lasting on average 11.86 days. Moreover, compared to sham-operated controls, ischemic female rats showed reduced Kiss1 expression in the hypothalamic ARC and POA, concomitant with elevated ERα in the ARC and increased GnIH in the DMH and CA1. Reduced GR expression in the CA1 was associated with increased GR-immunoreactivity in the PVN, indicative of lasting dysregulation of HPA axis activation. Together, these findings demonstrate GCI disruption of female rats' estrous cycle over multiple days, with a lasting impact on HPG axis regulators within the reproductive axis.

Short-Term Fish Oil Supplementation during Adolescence Supports Sex-Specific Impact on Adulthood Visuospatial Memory and Cognitive Flexibility.

Numerous studies have supported benefits of omega-3 supplementation using Menhaden fish oil (FO) to promote brain maturation and plasticity during critical developmental periods. The goal of this study was to determine sex-specific immediate and delayed impact of adolescent omega-3 supplementation on visuospatial memory and cognitive flexibility. Sixty-four Wistar rats (n = 32 males and females) received daily FO or soybean oil (CSO) supplementation via oral gavage (0.3 mL/100 g body weight) from postnatal day 28-47. The Barnes Maze Test (BMT) was used to measure visuospatial memory and reversal learning trials (RL) determined cognitive flexibility. Juveniles underwent testing immediately after the gavage period, while adults began testing on postnatal day 90. Adult rats showed reduced working memory errors (WME) and gradual decrease in escape latencies compared to juveniles. Importantly, adult FO-supplemented females displayed fewer WME than males, while males' performance benefited from CSO supplementation. Overall, sex- and supplementation-dependent effects supported a positive impact of FO in female rats only. Our findings support the potential for supplementation limited to the early adolescence period to influence adulthood spatial learning and cognitive flexibility in a sex-specific manner.

Women with Myocardial Infarction Present Subtle Cognitive Difficulties on a Neuropsychological Battery After Exposure to a Social Stressor.

Objective: Myocardial infarction (MI) is the primary cause of mortality and morbidity in women, but its sequelae remain largely understudied. Given the heart-brain relationship, our study aimed to further understand stress's impact on regulating cognitive function post-MI. Specifically, our study evaluated the effect of stress induced using the Trier Social Stress Test (TSST), on neuropsychological function in women who have or have not experienced MI. Methodology: To do so, women (mean age = 59.41 yrs) with (WHxMI = 13) or without () a history of MI were exposed to the TSST prior to completion of a series of standardized neuropsychological tests: the Montreal Cognitive Assessment (MoCA), Control Oral Word Association (COWA), Rey Complex Figure and Recognition (RCFT), Trail Making Test (TMT), and Auditory Consonant Triagrams (ACT). Results: Our findings support MI to be associated with impairments in working memory affecting immediate recall of ACT, as well as visuospatial impairments in the RCFT copy trial, marked by poorer drawing accuracy and incorrect placement of figure elements. Overall, WHxMI required more time to complete the neuropsychological assessment (WHxMI 166.57 ± 12, 155.00 ± 6.57; p < 0.01). Conclusion: Together, these findings support cognitive impairments noted following a social stressor to remain subtle in WHxMI. Our study highlights the need for the development of more sensitive tools to screen for neuropsychological impairments in women with MI and the importance of assessing performance in a variety of testing conditions.

Contribution of Obstructive Sleep Apnoea to Cognitive Functioning of Males With Coronary Artery Disease: A Relationship With Endocrine and Inflammatory Biomarkers.

Introduction: Our exploratory study aimed to determine whether obstructive sleep apnoea (OSA) could affect cognitive functioning in males with coronary artery disease (CAD), and whether such impact could be associated with changes in thyroid hormones and inflammatory marker regulation on cognitive functioning. Method: We evaluated different endocrine and inflammatory biomarkers, including free triiodothyronine [fT3], free tetraiodothyronine [fT4], N-terminal pro-B-type natriuretic peptide [NT-pro-BNP], and high-sensitivity C-reactive protein [hs-CRP] serum levels in 328 males ( x ¯ = 57 ± 10 years), undergoing cardiac rehabilitation after an acute coronary event. Participants underwent full-night polysomnography and were classified in mild/non-OSA (n = 253) and OSA (n = 75) according to an apnoea-hypopnoea index ≥ 15 event/h. Cognitive functioning testing included the Digit Span Test, Digit Symbol Test (DSST), and Trail Making Test. Analyses of variance assessed the impact of OSA on cognitive functioning and possible relationships of fT3/fT4, NT-pro-BNP and with hs-CRP on cognitive measures. Results: Significant group (OSA, mild/non-OSA) × NT-pro-BNP (<157.0 vs. ≥157.0, ng/L) interactions were found for the DSST raw score (F (2,324) = 3.58, p = 0.014). Decomposition of interactions showed that the DSST scores of the OSA group with NT-pro-BNP ≥ 157.0 ng/L (M = 33.2; SD = 8.1) were significantly lower, p = 0.031, than those of the mild/non-OSA with NT-pro-BNP < 157.0 ng/L (M = 37.7; SD = 8.9). Conclusion: These findings indicate that males with OSA and clinically elevated NT-pro-BNP levels experienced inferior psychomotor performance compared to those without OSA and reduced NT-pro-BNP levels.

Delivery method matters: omega-3 supplementation by restricted feeding period and oral gavage has a distinct impact on corticosterone secretion and anxious behavior in adolescent rats.

Objectives: Oral gavage and time-restricted feeding are common delivery methods for dietary supplementation to rodents. However, the stress associated with selected feeding regimens could represent a confounding variable. In rodents, the adolescence period is particularly vulnerable to stressful events, in part related to ongoing maturation of the brain. In this context, omega-3 dietary supplementation has shown beneficial effects on neuronal growth, cognitive performance and stress regulation, while high-fat diet (HVF) has been associated with enhanced stress and anxiety. Therefore, this study has two aims: (1) evaluate the influence of 21-day supplementation with soybean oil (control group; CSO), fish oil (FO) or hydrogenated vegetable fat (HVF) fatty acids (FA) during the adolescence period on corticosterone secretion and anxiety-like behavior and, (2) compare the impact of dietary supplementation using oral gavage or time-limited feeding on these measures.Methods: Oral gavage or restricted feeding were used to daily feed adolescent rats (PND28-47; n = 49). On supplementation days 1, 7, 14 and 21, droplets of blood were collected for corticosterone (CORT) assessments. The Open Field (OFT) and the Elevated-Plus Maze (EPM) tests served to assess anxiety-like behavior on PND50.Results: Our findings indicate increased CORT secretion in restricted-(R) compared to gavage-fed animals on DAY7 and DAY14, suggesting heightened HPA-axis reactivity. Notably, CORT secretion diminished in FO-R-rats (DAY21), suggesting improved coping/adjustment. Consistent with CORT assessments, findings in the OFT and EPM supported attenuated anxiety in gavage versus restricted groups. FO and CSO supplementation reduced anxiety compared to HVF intake.Conclusions: Our findings uncover a significant impact of feeding methods on anxiety-like behavior and physiological stress response in rodents, supporting oral gavage as a less stressful option during the adolescent developmental stage. Supplement-specific effects on CORT secretion further indicated an influence of fish oil in regulating the stress response.

Predictive value of baseline cognitive functioning on health-related quality of life in individuals with coronary artery disease: a 5-year longitudinal study.

AIMS: Emerging studies suggest an association exists between coronary artery disease (CAD) and the development of neurodegenerative diseases, with CAD acting as a precursor. Our study aimed to investigate the relationship between baseline measures of cognitive functioning and long-term health-related quality of life (HRQoL) in individuals with CAD with specification to Type D personality traits and sex. METHODS AND RESULTS: This prospective observational cohort study consisted of 864 participants (mean age 58 SD = 9 years, 74.0% men) with CAD after acute coronary syndrome. Baseline characteristics included comprehensive cognitive testing, measures of sociodemographic and clinical factors, and psychological assessment scales, such as Type D personality scale and the Hospital Anxiety and Depression scale. The Minnesota Living with Heart Failure Questionnaire assessed participants' HRQoL, conducted through phone interviews at baseline, every 6 months for up to 2 years, and after 5 years. Cognitive functioning correlated with HRQoL at all time intervals over the 5-year follow-up. Regarding sex and Type D personality, significant differences emerged in associations between impaired cognitive functioning at baseline and HRQoL measured over the period of 5 years. Men participants with characteristics of Type D personality were especially vulnerable to impaired cognitive functioning affecting the 5-year quality of life. CONCLUSION: Men with CAD who obtained scores indicating characteristics of Type D personality were significantly more likely to have lower baseline cognitive functions and long-term HRQoL outcomes. This information could inform healthcare practitioners to screen for personality characteristics and closely follow-up those at a greater risk.

Global cerebral ischemia in adolescent male Long Evans rats: Effects of vanillic acid supplementation on stress response, emotionality, and visuospatial memory.

The developmental period is critical in delineating plastic response to internal and external events. However, neurobehavioural effects of global cerebral ischemia (GCI) in the maturing brain remain largely unknown. This study characterised the effects of GCI experienced at puberty on adulthood (1) hippocampus CA1 neuronal damage, (2) cognitive and emotional impairments, and (3) glucocorticoid receptor (GR) expression. Effects of adolescent exposure to the phenol vanillic acid (VA) on post-ischemic outcomes were also determined. Male Long Evans rats (n = 35) were supplemented for 21 consecutive days (postnatal days 33-53) with VA (91 mg/kg) or nut paste vehicle (control) prior to a 10-min GCI or sham surgery. As adults, rats were tested in the Open Field Test (OFT), Elevated-Plus Maze (EPM), and Barnes Maze (BM). GR expression was determined in the basolateral amygdala (BLA), CA1, and paraventricular nucleus (PVN), and brain injury assessed via CA1 neuronal density. Adolescent GCI exposure induced extensive hippocampal CA1 injury, which was not prevented by VA supplementation. Behaviourally, GCI increased EPM exploration while having no impact on spatial memory. VA intake increased OFT peripheral exploration. Notably, while no delayed changes in CA1 and PVN GR immunoreactivity were noted, both treatments separately increased BLA GR expression when compared with sham-nut paste rats. Age at GCI occurrence plays a critical role on post-ischemic impairments. The observation of minimal functional impairments despite important CA1 neuronal damage supports use of compensatory mechanisms. Our findings also show daily VA supplementation during adolescence to have no protective effects on post-ischemic outcomes, contrasting adult intake.

Global Cerebral Ischemia in Male Long Evans Rats Impairs Dopaminergic/ΔFosB Signalling in the Mesocorticolimbic Pathway Without Altering Delay Discounting Rates.

Global cerebral ischemia (GCI) in rats has been shown to promote exploration of anxiogenic zones of the Elevated-Plus Maze (EPM) and Open Field Test (OFT). This study investigated changes in impulsive choice and/or defensive responses as possible contributors of heightened anxiogenic exploration observed after ischemia. Impulsivity was assessed using delay discounting (DD) paradigms, while the Predator Odour Test (PO) served to assess changes in defensive responses towards a naturally aversive stimulus. Male Long Evans rats underwent 9 days of autoshaping training and 24 days of DD training prior to GCI or sham surgery (n = 9/group). Post-surgery, rats completed the OFT, EPM, and PO, followed by 6 days of DD sessions. Blood droplets served to evaluate corticosterone secretion associated with PO exposure. With impulsivity being regulated through mesocorticolimbic monoaminergic pathways, we also characterised post-ischemic changes in the expression of dopamine D2 receptors (DRD2), dopamine transporters (DAT), and 1FosB in the basolateral amygdala (BLA), nucleus accumbens core (NAcC) and shell (NAcS), and ventromedial prefrontal cortex (vmPFC) using immunohistofluorescence. Our findings revealed no impact of GCI on delay discounting rates, while PO approach behaviours were minimally affected. Nonetheless, GCI significantly reduced DRD2 and ΔFosB-ir in the NAcS and NAcC, respectively, while DAT-ir was diminished in both NAc subregions. Collectively, our findings refine the understanding of cognitive-behavioural and biochemical responses following stroke or cardiac arrest. They support significant alterations to the dopaminergic mesocorticolimbic pathway after ischemia, which are not associated with altered impulsive choice in a DD task but may influence locomotor exploration of the OFT and EPM.

Adult Male Rats Show Resilience to Adolescent Bisphenol A Effects on Hormonal and Behavioral Responses While Co-Exposure With Hop Extracts Supports Synergistic Actions.

The adolescence period, marked by sexual and brain maturation, has shown sensitivity to various environmental disruptors. Exposure to the xenoestrogen bisphenol A (BPA) is known to alter physiological and behavioral responses although its role at this critical period remains largely unknown. Recent research further suggests biochemical and genomic effects of BPA to be mitigated by various natural compounds, while effects on behavior have not been examined. This study aimed to characterize (1) the effects of dietary BPA during adolescence on endogenous corticosterone (CORT) secretion, emotional behavior, and testosterone (T) in adulthood, and (2) the impact of combined exposure to BPA with hop extracts (Hop), a phytoestrogen with anxiolytic properties. To do so, four groups of male Wistar rats [postnatal day (PND) 28] were administered corn oil (control), BPA (40 mg/kg), hops (40 mg/kg), or BPA-hops by oral gavage for 21 days (PND 28-48). Blood droplets collected on PND 28, 48, and 71 served to measure CORT and T changes. As adults, rats were tested in the elevated plus maze (EPM), the social interaction test, and the forced swim test. Our findings demonstrated elevated anxiety and a trend toward depressive-like behaviors in BPA- compared to hops-exposed rats. However, BPA intake had no impact on basal CORT levels, or adulthood T secretion and sociability. Of note, BPA's anxiogenic effect manifested through decreased EPM open arm entries was abolished by hops co-supplementation. Together, our observations suggest the adolescence period to be less sensitive to deleterious effects of BPA than what has been reported upon gestational and perinatal exposure.

Sex-specific differences in adult cognition and neuroplasticity following repeated combinatory stress and TrkB receptor antagonism in adolescence.

Evidence supports brain-derived neurotrophic factor (BDNF) and its primary receptor tyrosine-related kinase B (TrkB) as targets in the treatment of mood disorders. This study characterized the impact of a 10-day combinatory stress paradigm (alternating days of restraint stress and forced swim) and administration of the selective TrkB antagonist ANA-12 (0.5 mg/kg, i.p.) during adolescence in male and female Wistar rats on adulthood behavioral and neurochemical responses. The social interaction/preference (SIT/SP), and Y maze conditioned place preference (YMCPP) and passive avoidance tests (YMPAT), initiated on PND 62, served to determine sex-related behavioral responses. Results support reduced sociability in females in the SIT/SP, but no impact of ANA-12 to regulate sociability or social memory. Blockade of TrkB during adolescence facilitated YMCPP-related reward behavior in both sexes, and reduced YMPAT fear conditioning in females. Following behavioral testing, rats were exposed to 5-min acute forced swim and brains collected 2 h post swim to determine effects of adolescent TrkB blockade and stress exposure on neurochemical regulators of stress and plasticity. Findings show elevated glucocorticoid receptor (GR-) and TrkB-immunoreactivity (ir) in the amygdalar central nucleus, and GR-ir in the hypothalamic paraventricular nucleus of females compared to males. In the hippocampal CA1, BDNF-ir was lower in females versus males, and GR-ir was elevated in stress versus non-stress males. Together, we demonstrate that inherent sex-specific differences, which may modulate impact of adolescence stress exposure and TrkB inhibition, differentially affect male and female adulthood behavior and biochemical response profiles, suggesting that these responses are in part conditioned by prior experience.

Increase serum cortisol in young guinea pig offspring in response to maternal iron deficiency.

Iron deficiency (ID) has been reported as a risk factor in the pathology of attention-deficit/hyperactivity disorder, although the mechanisms seem unclear. Previous results from our research group showed that guinea pig offspring born from ID dams were significantly more active in the Open Field Test than the controls. This behavior could potentially be associated to stress. We therefore hypothesized that maternal iron deficiency (MID) elevates the offspring serum cortisol, a biomarker of stress, during childhood and possibly at mature age. Twenty-four female guinea pigs were fed an iron-sufficient (IS) diet (114 mg/kg) or ID diet (11.7 mg/kg) during the gestation and lactation. Pups in both groups were weaned at postnatal day (PNd) 9 and given an IS diet. Hematocrit and serum cortisol levels were measured in dams at every trimester of gestation and in pups at PNd24 and 84. We found no impact of MID on dam's cortisol values. However, our findings indicate that MID increased cortisol secretion in the offspring during childhood, cortisol values being significantly elevated in ID than IS pups at PNd24 (P < .05). During adulthood (PNd84), both groups showed comparable cortisol levels. The elevated cortisol secretion observed in the offspring born from ID mothers during childhood may indicate increased stress reactivity which may have contributed to the higher level of activity when tested in a novel open environment. These findings suggest that MID can potentially act as internal stressor affecting the early development conceivably leading to increased stress levels in the children.

Sex-specific differences in corticosterone secretion, behavioral phenotypes and expression of TrkB.T1 and TrkB.FL receptor isoforms: Impact of systemic TrkB inhibition and combinatory stress exposure in adolescence.

Stress exposure has been implicated in the development of mood disorders, although little is known about the lasting effects of repeated stress during the adolescent period on sex-specific differences in endocrine and plasticity-signaling responses in adulthood. Using a 10-day combinatory stress paradigm (postnatal day (PND) 26 to 35), we examined sex-specific impact of adolescent stress and inhibition of tyrosine-related kinase B (TrkB) receptor (ANA-12; 0.5 mg/kg, i.p.) on 1) adolescent blood corticosterone levels, 2) adult locomotion and anxiety-like behavior, and 3) region-specific differences in endogenous TrkB full-length (TrkB.FL) and truncated (TrkB.T1) receptor isoforms. Blood collected on days 1, 5 and 10 revealed elevated basal and stress-induced CORT secretion in females compared to males, while ANA-12 attenuated CORT elevations post stress in both sexes. As adults, all females exhibited higher locomotor and exploratory activity than males in the open field test and elevated plus maze, and differences were comparable in the forced swim within stress-naïve and stress groups. Biochemically, vehicle-treated males showed elevated TrkB.T1 and TrkB.FL compared to vehicle-treated females in the PFC, hippocampus and NAc, and levels were consistently attenuated by ANA-12 treatment in non-stress males. With regards to stress exposure, expression of both isoforms was strongly down-regulated in the NAc of males only and was associated with increased TrkB.T1 in the PFC. ANA-12 enhanced expression in females, independent of stress exposure, compared to vehicle-treated counterparts, expression being increased for TrkB.T1 versus TrkB.FL and magnitude of the changes being region-specific. In contrast, ANA-12 effects in stressed males were restricted to inhibition of both isoforms in the hippocampus. Together, our findings support that TrkB activation, contingent on stress exposure, differentially affects TrkB isoform regulation during adulthood. Sex-specific biochemical responses at delayed intervals following adolescent stress exposure further support the need to include the sex variable in animal models.

Inhibition of TrkB at the nucleus accumbens, using ANA-12, regulates basal and stress-induced orexin A expression within the mesolimbic system and affects anxiety, sociability and motivation.

Repeated stress exposure can lead to the development of anxiety and mood disorders. An emerging biological substrate of depression and associated pathology is the nucleus accumbens (NAc), which through interactions with limbic, cognitive and motor circuits can regulate a variety of stress responses. Within these circuits, orexin neurons are involved in arousal and stress adaptability, effects proposed mediated via brain-derived neurotrophic factor signaling. This study tested the hypotheses that 1) repeated exposure to heterotypic stress alters social ability and preference and passive avoidant behaviors, 2) TrkB receptors at the NAc shell regulates stress-induced behavioral responses and orexin expression within the mesocorticolimbic system. Our findings indicate that ANA-12 (0.25 µg/0.5 µl) enhanced sociability during the social interaction test, although treatment had no effect on social preference. The development of conditioned place preference, and fear retention in the passive avoidance test were also facilitated by ANA-12. Biochemical assessments on brain tissues collected within 2 h of a forced swim exposure revealed that ANA-12 increased orexin A immunoreactivity (ir) in the hypothalamic perifornical area, while expression was reduced in the ventral portion of the hippocampal CA1 layer, irrespective of the stress condition. This contrasts changes at the VTA characterized by elevated versus reduced orexin A-ir in ANA-12-treated stress and non-stress rats, respectively. Colocalized orexin A- and tyrosine hydroxylase (TH)-ir at the VTA supports a different temporal expression post stress, TH-ir being unaffected 9 days post stress. These findings support a role for TrkB receptors in regulating basal and stress-induced social, cognitive and motivational behavior, and modulatory actions of BDNF, via TrkB signaling, on orexin A signaling upon stress exposure.

CRHR1 exacerbates the glial inflammatory response and alters BDNF/TrkB/pCREB signaling in a rat model of global cerebral ischemia: implications for neuroprotection and cognitive recovery.

This study examined the impact of corticotropin-releasing hormone type 1 receptor (CRHR1) blockade using Antalarmin (ANT) on the expression of markers of neuroplasticity and inflammation, as well as neuroprotection and behavioral recovery following global cerebral ischemia. Male Wistar rats (N=50) were treated with ANT (2µg/2µl; icv) or a vehicle solution prior to a sham or four vessel (4VO) occlusion. Seven days post ischemia, anxiety was assessed in the Elevated Plus Maze and Open Field tests, and fear and spatial learning in a Y-Maze Passive Avoidance Task and the Barnes Maze. Thirty days post ischemia, brain derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) receptor expression, hippocampal neuronal death and inflammation were determined by analyzing immunoreactivity (ir) of neuron-specific nuclear protein (NeuN), microglia (IBA1, ionized calcium binding adaptor molecule 1), astrocytes (GFAP, glial fibrillary acidic protein) and TNFα (tumor necrosis factor alpha) a pro-inflammatory cytokine. Our findings revealed that ANT improved behavioral impairments, while conferring neuroprotection and blunting neuroinflammation in all hippocampal sub-regions post ischemia. We also observed reduced BDNF and TrkB mRNA and protein levels at the hippocampus, and increased expression at the hypothalamus and amygdala post ischemia, site-specific alterations which were regularized by pre-ischemic CRHR1 blockade. These findings support that CRHR1 actively contributes to altered brain plasticity, neuronal inflammation and injury and recovery of function following ischemic brain insults.

Blockade of TrkB receptors in the nucleus accumbens prior to heterotypic stress alters corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway.

Inhibition of stress-induced elevations in brain-derived neurotrophic factor (BDNF) or its primary receptor tyrosine-related kinase B (TrkB) within the reward pathway may modulate vulnerability to anxiety and mood disorders. The current study examined the role of BDNF/TrkB signaling on biochemistry and behavior under basal conditions and following exposure to a 10-day heterotypic stress paradigm in male rats. Effects of intra-accumbal administration of TrkB antagonist ANA-12 (0.25µg/0.5µl/min) on anxiety, and expression of Trk-B, corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2) and glucocorticoid receptor (GR) within the mesolimbic pathway were determined. Notably, ANA-12 attenuated anxiety-like behavior in stress rats while increasing anxiety in the non-stress group in the elevated plus maze (EPM). At the neurochemical level, ANA-12 blocked the increased vGluT2 and CRH expressions in the hypothalamic PVN and basolateral amygdala in stress rats, while it enhanced vGluT2 and CRH expressions in non-stress rats. ANA-12 also showed state-dependent effects at the NAc core, attenuating TrkB-ir in non-stress rats while reversing reduced expression in stressed rats. At the cingulate cortex, ANA-12 normalized stress-induced increase in TrkB expression. Notably, ANA-12 showed region-specific effects on GR-ir at the NAc core and shell, with increased GR-ir in non-stress rats, although the drug attenuated stress-induced GR-ir expression only in the core portion of the NAc, while having no impact at the cingulate cortex. Elevated blood CORT levels post-stress was not influenced by ANA-12 treatment. Together, these findings suggest that BDNF-mediated TrkB activation exerts differential impact in regulating emotional response under basal and stress conditions.

Activation of CRHR1 receptors regulates social and depressive-like behaviors and expression of BDNF and TrkB in mesocorticolimbic regions following global cerebral ischemia.

Increased HPA axis activation and CRH release characterize the brain's response to global cerebral ischemia. Recently, CRH via activation of CRH type 1 receptors (CRHR1) has been shown to regulate Brain Derived Neurotrophic Factor (BDNF) secretion and emotional behavior. The current study investigates the impact of CRHR1 blockade on BDNF/TrkB signaling expression in the mesolimbic circuitry, and social and depressive-like behavior following global ischemia. Adult male Wistar rats were injected with Antalarmin (2µg/µl) or a vehicle 30min prior to 10min global cerebral ischemia (4VO model) or sham occlusion. The Three Chamber Social Approach Test (SIT) assessed sociability and preference for social novelty, and the novelty suppressed feeding test (NSFT), forced swim test (FST), and sucrose preference test characterized anxiety and depression. Corticosterone levels and organ (thymus, seminal and adrenal glands) weights were determined as additional physiological indices of stress. Immunohistochemistry, Western blot and Rt-PCR were used to assess BDNF and TrkB receptor levels in subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and ventral tegmental area (VTA) 30days post-ischemia. Our findings indicate reduced BDNF and TrkB protein and mRNA expression in the mPFC post-ischemia, while heightened levels were found in the NAc. Ischemia increased immobility in the FST and reduced sucrose preference and led to reduced latency to feed in the NSFT and heightened sociability and social novelty preference in the SIT. Antalarmin treatment normalized post-ischemic biochemical/behavioral changes. Our findings support lasting effects of CRHR1 activation on brain plasticity markers, likely playing a role in emotional impairments following cardio- or cerebro-vascular accidents.

Endocannabinoid CB1 receptor activation upon global ischemia adversely impact recovery of reward and stress signaling molecules, neuronal survival and behavioral impulsivity.

Global cerebral ischemia in rodents, which mimics cardiac arrest in humans, is associated with a surge in endocannabinoids and increased transmission of dopamine and glutamate leading to excitotoxic cell death. The current study assessed the role of CB1 receptor activation at the moment of an ischemic insult on ensuing regulation of stress and reward signaling molecules, neuronal injury and anxiety-like behavior. Male Wistar rats were separated into 4 groups (n=10/group); sham and ischemic rats administered the CB1 endocannabinoid receptor antagonist AM251 (2mg/kg, i.p.) 30min prior to global cerebral ischemia, and vehicle-treated counterparts. The effects of CB1 receptor blockade on corticotropin-releasing hormone (CRH), vesicular glutamate transporter 2 (vGluT2), tyrosine hydroxylase (TH) and dopamine receptor 1 (DRD1) signaling expression, together with CA1 neuronal damage and anxiety-like behaviors were assessed. Our findings show attenuated CA1 injury and behavioral deficits in AM251-treated ischemic rats. AM251-pretreatment also partially or completely reversed ischemia-induced alterations in TH-ir expression at the hippocampus, ventral tegmental area (VTA), nucleus accumbens (NAc) and basolateral amygdala (BLA), normalized DRD1-ir at the medial forebrain bundle, and diminished BLA and PVN-CRH expression. All groups showed comparable vGluT2 expression at the BLA and PVN-parvocellular subdivision. These findings support a determinant role of CB1 receptor activation at time of ischemia on functional recovery. They also support "state-dependent" effects of endocannabinoids, raising considerations in the development of effective molecules to regulate HPA axis function and mood disorders following cardiac arrest and stroke.

Dose-related effects of chronic resveratrol administration on neurogenesis, angiogenesis, and corticosterone secretion are associated with improved spatial memory retention following global cerebral ischemia.

OBJECTIVES: The polyphenol resveratrol has shown regulatory effects on hippocampal neurogenesis, which according to the neurovascular niche hypothesis, is likely to involve stimulation of angiogenesis. In rodents, global cerebral ischemia leads to selective CA1 neuronal damage, spatial memory impairments, lasting changes in corticosterone (CORT) secretion, and increased neurogenesis. This study examined dose-related effects of 21-day RSV treatment on markers associated with neurogenesis (DCX, PSA-NCAM) and angiogenesis (CD31) in the hippocampus at short (7-day) and long-term (85-day) intervals following global ischemia. In parallel, post-ischemic and stress-induced CORT levels and spatial memory in the Morris water maze were determined. METHODS: Five groups of male Wistar rats were included: sham/saline, ischemia/saline, ischemia/1 mg/kg RSV, ischemia/10 mg/kg RSV, and sham/10 mg/kg RSV. Changes in expression of plasticity markers were paralleled by assessment of basal- and stress-induced CORT secretions, and spatial memory performance. RESULTS: Our findings revealed a significant attenuation of ischemia-induced DCX/PSA-NCAM expression in RSV-treated rats, whereas RSV treatment increased angiogenesis in the injured CA1 region. RSV attenuated CORT levels 3 days post-ischemia and a trend toward attenuating CORT secretion in response to 15 minutes restraint stress. Increased swimming latencies in the target quadrant during the MWM probe trial in RSV-treated ischemic rats support beneficial effects of RSV on spatial memory retention. DISCUSSION: Our findings uncover time- and dose-related effects of RSV and global ischemia on the regulation of hippocampal plasticity. Changes in neuro- and angiogenesis are consistent with RSV neuroprotective effects, but appear independent of RSV regulatory effects on corticosterone secretion.

Resveratrol downregulates type-1 glutamate transporter expression and microglia activation in the hippocampus following cerebral ischemia reperfusion in rats.

The naturally occurring polyphenol phytoalexin resveratrol (RSV) regulates neuronal inflammation in various disease models and protects the brain against ischemic injury. Cell surface glutamate transporters on perisynaptic astrocytes are important regulators of extracellular glutamate levels and synaptic activation. Following cerebral ischemia, reduced astroglial type-1 glutamate transporter (GLT-1) expression in the CA1 pyramidal layers of the hippocampus contribute to neurotoxic glutamate levels. The current study examined the effects of 21-day RSV pretreatment (1 or 10mg/kg dose; i.p.) on microglia and astrocyte activation and characterized GLT-1 expression in the dentate gyrus (DG), CA1 and CA3 layers of the hippocampus 7 days following 10min global ischemia. Male Wistar rats were divided into five groups; sham/saline, ischemia/saline, ischemia/1mg/kg RSV, ischemia/10mg/kg RSV and sham/10mg/kg RSV. Immunohistochemical detection of GLT-1, CD11b/c, glial fibrillary acidic protein (GFAP) assessed type 1 glutamate transporter expression and microglial/glial cell activation following sham surgery or global ischemia. Our findings demonstrate prevention by RSV of ischemia-induced reduction of GLT-1 expression in the vulnerable CA1 layer 7 days following global ischemia, which was accompanied by the polyphenol's inhibition of post ischemic increase in CD11b/c and GFAP expression. RSV also conferred significant CA1 neuronal protection positively correlated with attenuation of glutamate transporter activation. These findings support beneficial effects of RSV in modulation of the excitotoxic cascade postischemia, which are congruent with anti-inflammatory effects observed in various pathological models.