Inhibition of prefrontal glutamatergic neuron activity during the recovery period following chronic stress disrupts fear memory in male rats: potential role of the infralimbic cortex.

Chronic stress typically leads to deficits in fear extinction. However, when a delay occurs from the end of chronic stress and the start of fear conditioning (a "recovery"), rats show improved context-cue discrimination, compared to recently stressed rats or nonstressed rats. The infralimbic cortex (IL) is important for fear extinction and undergoes neuronal remodeling after chronic stress ends, which could drive improved context-cue discrimination.

Corticosterone disrupts spatial working memory during retention testing when highly taxed, which positively correlates with depressive-like behavior in middle-aged, ovariectomized female rats.

Major Depressive Disorder affects 8.4 % of the U.S.

Chronic stress leads to persistent and contrasting stellate neuron dendritic hypertrophy in the amygdala of male and female rats, an effect not found in the hippocampus.

In males, chronic stress enhances dendritic complexity in the amygdala, a region important in emotion regulation. An amygdalar subregion, the basolateral amygdala (BLA), is influenced by the hippocampus and prefrontal cortex to coordinate emotional learning and memory. This study quantified changes in dendritic complexity of BLA stellate neurons ten days after an unpredictable chronic stressor ended in both male and female rats.

Bruce S. McEwen and his continued legacy.

A commentary on 'Doctor, I am so stressed out!' A descriptive study of biological, psychological, and socioemotional markers of stress in individuals who self-identify as being 'very stressed out' or 'zen'.

Estrous Cycle Modulation of Feeding and Relaxin-3/Rxfp3 mRNA Expression: Implications for Estradiol Action.

Introduction: Food intake varies during the ovarian hormone/estrous cycle in humans and rodents, an effect mediated mainly by estradiol. A potential mediator of the central anorectic effects of estradiol is the neuropeptide relaxin-3 (RLN3) synthetized in the nucleus incertus (NI) and acting via the relaxin family peptide-3 receptor (RXFP3).

Methods: We investigated the relationship between RLN3/RXFP3 signaling and feeding behavior across the female rat estrous cycle.

Chronic stress has different immediate and delayed effects on hippocampal calretinin- and somatostatin-positive cells.

Past studies find that chronic stress alters inhibitory, GABAergic circuitry of neurons in distinct hippocampal subregions. Less clear is whether these effects persist weeks after chronic stress ends, and whether these effects involve changes in the total number of hippocampal GABAergic neurons or modulates the function of specific GABAergic subtypes. A transgenic mouse line (VGAT:Cre Ai9) containing an indelible marker for GABAergic neurons (tdTomato) throughout the brain was used to determine whether chronic stress alters total GABAergic neuronal number or the expression of two key GABAergic cell subtypes, calretinin expressing (CR+) and somatostatin expressing (SOM+) neurons, and whether these changes endure weeks later.

Chronic stress has lasting effects on improved cued discrimination early in extinction.

Chronic stress typically leads to deficits in fear extinction when tested soon after chronic stress ends. Given the importance of extinction in updating fear memories, the current study examined whether fear extinction was impaired in rats that were chronically stressed and then given a break from the end of chronic stress to the start of fear conditioning and extinction. Male rats were chronically stressed by restraint (6 h/d/21 d) and tested soon (termed immediate, STR-IMM), or 3 or 6 wk after a rest period from restraint (termed rest or "R," STR-R3, STR-R6).

Chronic unpredictable intermittent restraint stress disrupts spatial memory in male, but not female rats.

Chronic stress leads to sex-dependent outcomes on spatial memory by producing deficits in males, but not in females. Recently it was reported that compared to daily restraint, intermittent restraint (IR) produced more robust stress and anxiety responses in male rats. Whether IR would be sufficiently robust to impair hippocampal-dependent spatial memory in both male and female rats was investigated.

A long-term cyclic plus tonic regimen of 17β-estradiol improves the ability to handle a high spatial working memory load in ovariectomized middle-aged female rats.

The influence of estrogens on modifying cognition has been extensively studied, revealing that a wide array of factors can significantly impact cognition, including, but not limited to, subject age, estrogen exposure duration, administration mode, estrogen formulation, stress history, and progestogen presence. Less known is whether long-term, extended exposure to estrogens would benefit or otherwise impact cognition. The present study examined the effects of 17β-estradiol (E2) exposure for seven months, beginning in late adulthood and continuing into middle age, using a regimen of cyclic exposure (bi-monthly subcutaneous injection of 10 μg E2), or Cyclic+Tonic exposure (bi-monthly subcutaneous injection of 10 μg E2 + Silastic capsules of E2) in ovariectomized female Fischer-344-CDF rats.

The differential role of the dorsal hippocampus in initiating and terminating timed responses: A lesion study using the switch-timing task.

This study investigated the role of the dorsal hippocampus (dHPC) in the temporal entrainment of behavior, while addressing limitations of previous evidence from peak procedure experiments. Rats were first trained on a switch-timing task in which food was obtained from one of two concurrently available levers; one lever was effective after 8 s and the other after 16  s. After performance stabilized, rats underwent either bilateral NMDA lesions of the dHPC or sham lesions.

The Noonan Syndrome-linked Raf1L613V mutation drives increased glial number in the mouse cortex and enhanced learning.

RASopathies are a family of related syndromes caused by mutations in regulators of the RAS/Extracellular Regulated Kinase 1/2 (ERK1/2) signaling cascade that often result in neurological deficits. RASopathy mutations in upstream regulatory components, such as NF1, PTPN11/SHP2, and RAS have been well-characterized, but mutation-specific differences in the pathogenesis of nervous system abnormalities remain poorly understood, especially those involving mutations downstream of RAS. Here, we assessed cellular and behavioral phenotypes in mice expressing a Raf1L613V gain-of-function mutation associated with the RASopathy, Noonan Syndrome.

BDNF and TrkB Mediate the Improvement from Chronic Stress-induced Spatial Memory Deficits and CA3 Dendritic Retraction.

The brain is capable of improving from a chronically stressed state. The hippocampus in particular appears to "recover" from chronic stress-induced morphological and functional deficits following a post-stress rest period of several weeks. We previously found that hippocampal brain-derived neurotrophic factor (BDNF) was necessary for spatial ability to improve following a post-stress rest period.

The impact from the aftermath of chronic stress on hippocampal structure and function: Is there a recovery?

Chronic stress results in functional and structural changes to the brain and especially the hippocampus. Decades of research have provided insights into the mechanisms by which chronic stress impairs hippocampal-mediated cognition and the corresponding reduction of hippocampal CA3 apical dendritic complexity. Yet, when chronic stress ends and time passes, which we refer to as a "post-stress rest period," hippocampal-mediated spatial memory deficits begin to improve and CA3 apical dendritic arbors increase in complexity.

Antagonizing the GABA receptor during behavioral training improves spatial memory at different doses in control and chronically stressed rats.

Chronic stress leads to a dysregulated inhibitory tone that could impact hippocampal-dependent spatial learning and memory. The present study examined whether spatial memory deficits resulting from chronic stress could be overcome by antagonizing the GABA receptor, a prominent inhibitory receptor of GABA in the hippocampus. Young adult male Sprague-Dawley rats were chronically stressed (STR, wire mesh restraint, 6h/d/21d) or placed in a no-stress control group (CON).

Chronic stress and hippocampal dendritic complexity: Methodological and functional considerations.

The current understanding of how chronic stress impacts hippocampal dendritic arbor complexity and the subsequent relationship to hippocampal-dependent spatial memory is reviewed. A surge in reports investigating hippocampal dendritic morphology is occurring, but with wide variations in methodological detail being reported. Consequently, this review systematically outlines the basic neuroanatomy of relevant hippocampal features to help clarify how chronic stress or glucocorticoids impact hippocampal dendritic complexity and how these changes occur in parallel with spatial cognition.

Early and Persistent Dendritic Hypertrophy in the Basolateral Amygdala following Experimental Diffuse Traumatic Brain Injury.

In the pathophysiology of traumatic brain injury (TBI), the amygdala remains understudied, despite involvement in processing emotional and stressful stimuli associated with anxiety disorders, such as post-traumatic stress disorder (PTSD). Because the basolateral amygdala (BLA) integrates inputs from sensory and other limbic structures coordinating emotional learning and memory, injury-induced changes in circuitry may contribute to psychiatric sequelae of TBI. This study quantified temporal changes in dendritic complexity of BLA neurons after experimental diffuse TBI, modeled by midline fluid percussion injury.

The prodrug DHED selectively delivers 17β-estradiol to the brain for treating estrogen-responsive disorders.

Many neurological and psychiatric maladies originate from the deprivation of the human brain from estrogens. However, current hormone therapies cannot be used safely to treat these conditions commonly associated with menopause because of detrimental side effects in the periphery. The latter also prevents the use of the hormone for neuroprotection.

Chronic stress enhanced fear memories are associated with increased amygdala zif268 mRNA expression and are resistant to reconsolidation.

The chronically stressed brain may present a vulnerability to develop maladaptive fear-related behaviors in response to a traumatic event. In rodents, chronic stress leads to amygdala hyperresponsivity and dendritic hypertrophy and produces a post traumatic stress disorder (PTSD)-like phenotype that includes exaggerated fear learning following Pavlovian fear conditioning and resistance to extinction. It is unknown whether chronic stress-induced enhanced fear memories are vulnerable to disruption via reconsolidation blockade, as a novel therapeutic approach for attenuating exaggerated fear memories.

Sex-specific impairment and recovery of spatial learning following the end of chronic unpredictable restraint stress: potential relevance of limbic GAD.

Chronic restraint stress alters hippocampal-dependent spatial learning and memory in a sex-dependent manner, impairing spatial performance in male rats and leaving intact or facilitating performance in female rats. Moreover, these stress-induced spatial memory deficits improve following post-stress recovery in males. The current study examined whether restraint administered in an unpredictable manner would eliminate these sex differences and impact a post-stress period on spatial ability and limbic glutamic acid decarboxylase (GAD65) expression.

Hippocampal brain-derived neurotrophic factor mediates recovery from chronic stress-induced spatial reference memory deficits.

Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain-derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the dorsal hippocampal cornu ammonis (CA)3 region with an adeno-associated viral vector containing the sequence for a short hairpin RNA (shRNA) directed against BDNF or a scrambled sequence (Scr).

Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder.

Chronic stress may impose a vulnerability to develop maladaptive fear-related behaviors after a traumatic event. Whereas previous work found that chronic stress impairs the acquisition and recall of extinguished fear, it is unknown how chronic stress impacts nonassociative fear, such as in the absence of the conditioned stimulus (CS) or in a novel context. Male rats were subjected to chronic stress (STR; wire mesh restraint 6 h/d/21d) or undisturbed (CON), then tested on fear acquisition (3 tone-footshock pairings), and two extinction sessions (15 tones/session) within the same context.

Experience-dependent effects of context and restraint stress on corticolimbic c-Fos expression.

Stressors are typically multidimensional, comprised of multiple physical and sensory components that rarely occur as single isolated events. This study used a 2-day stress exposure paradigm to assess functional activation patterns (by Fos expression) in key corticolimbic structures following repeated context, repeated restraint, context followed by restraint or restraint followed by context. On day 1, rats were transported to a novel context and either restrained for 6 h or left undisturbed.

Chronic stress impairs prefrontal cortex-dependent response inhibition and spatial working memory.

Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, the fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague-Dawley rats were first trained on the RAWM and subsequently trained on FMI.

Environmental enrichment protects against the effects of chronic stress on cognitive and morphological measures of hippocampal integrity.

Chronic stress has detrimental effects on hippocampal integrity, while environmental enrichment (EE) has beneficial effects when initiated early in development. In this study, we investigated whether EE initiated in adulthood would mitigate chronic stress effects on cognitive function and hippocampal neuronal architecture, when EE started one week before chronic stress began, or two weeks after chronic stress onset. Adult male Sprague Dawley rats were chronically restrained (6h/d) or assigned as non-stressed controls and subdivided into EE or non-EE housing.