Research over the past few decades has established a role for the endocannabinoid system in contributing to the neural and endocrine responses to stress exposure. The two endocannabinoid ligands, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), both play roles in regulating the stress response and both exhibit dynamic changes in response to stress exposure. Most of this previous research, however, was conducted in male rodents. Given that, especially in rodents, the stress response is influenced by sex, an understanding of how these dynamic responses of endocannabinoids in response to stress is influenced by sex could provide insight into sex differences of the acute stress response. We exposed adult, Sprague Dawley rats to different commonly utilized acute stress modalities, specifically restraint, swim and foot shock stress. Thirty minutes following stress onset, we excised the amygdala, hippocampus and medial prefrontal cortex, corticolimbic brain regions involved in the stress response, to measure endocannabinoid levels. When AEA levels were altered in response to restraint and swim stress, they were reduced, whereas exposure to foot shock stress led to an increase in the amygdala. 2-AG levels, when they were altered by stress exposure were only increased, specifically in males in the amygdala following swim stress, and in the hippocampus and medial prefrontal cortex overall following foot shock stress. This increase in 2-AG levels following stress only in males was the only sex difference found in stress-induced changes in endocannabinoid levels. There were no consistent sex differences observed. Collectively, these data contribute to our further understanding of the interactions between stress and endocannabinoid function.

Alcohol is a commonly used drug that can produce alcohol use disorders (AUDs). Few individuals with AUDs receive treatment and treatment options are complicated by issues with effectiveness and compliance. Alcohol has been shown to differentially affect specific brain regions and an improved understanding of circuit-specific dysregulation caused by alcohol is warranted. Previous work has implicated both the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in alcohol-associated plasticity, however studies directly examining the impact of alcohol exposure on this circuit are lacking. The current study employed an optogenetic strategy to investigate the prelimbic mPFC to BLA circuit and changes in circuit activity following chronic intragastric ethanol exposure in male Sprague Dawley rats. We observed monosynaptic connections with light-evoked stimulation of mPFC terminals in the BLA with efficacy and short latency. We also found that mPFC-BLA projections are primarily glutamatergic under basal inhibitory control, with a lesser population of GABAergic projections. We examined optically-evoked glutamate currents in the BLA using repeated trains of stimulation that displayed accommodation, or a reduction in evoked current amplitude over repeated stimulations. We found that following chronic ethanol exposure mPFC-BLA glutamatergic connections were dysregulated such that there were decreases in overall function, notably in synaptic strength and accommodation, with no change in probability of evoked glutamate release. The lesser GABAergic component of the mPFC-BLA circuit was not altered by chronic ethanol exposure. Collectively these data indicate that mPFC-BLA circuitry is a significant target of alcohol-associated plasticity, which may contribute to pathological behavior associated with AUDs.

Childhood adversity is thought to undermine youth socioemotional development via altered neural function within regions that support emotion processing. These effects are hypothesized to be developmentally specific, with adversity in early childhood sculpting subcortical structures (e.g., amygdala) and adversity during adolescence impacting later-developing structures (e.g., prefrontal cortex; PFC). However, little work has tested these theories directly in humans. Using prospectively collected longitudinal data from the Fragile Families and Child Wellbeing Study (FFCWS) (N = 4,144) and neuroimaging data from a subsample of families recruited in adolescence (N = 162), the current study investigated the trajectory of harsh parenting across childhood (i.e., ages 3 to 9) and how initial levels versus changes in harsh parenting across childhood were associated with corticolimbic activation and connectivity during socioemotional processing. Harsh parenting in early childhood (indexed by the intercept term from a linear growth curve model) was associated with less amygdala, but not PFC, reactivity to angry facial expressions. In contrast, change in harsh parenting across childhood (indexed by the slope term) was associated with less PFC, but not amygdala, activation to angry faces. Increases in, but not initial levels of, harsh parenting were also associated with stronger positive amygdala-PFC connectivity during angry face processing.

In recent years, a growing body of research has shown sex differences in the prevalence and symptomatology of psychopathologies, such as depression, anxiety, and fear-related disorders, all of which show high incidence rates in early life. This has highlighted the importance of including female subjects in animal studies, as well as delineating sex differences in neural processing across development. Of particular interest is the corticolimbic system, comprising the hippocampus, amygdala, and medial prefrontal cortex. In rodents, these corticolimbic regions undergo dynamic changes in early life, and disruption to their normative development is believed to underlie the age and sex-dependent effects of stress on affective processing. In this review, we consolidate research on sex differences in the hippocampus, amygdala, and medial prefrontal cortex across early development. First, we briefly introduce current principles on sexual differentiation of the rodent brain. We then showcase corticolimbic regional sex differences in volume, morphology, synaptic organization, cell proliferation, microglia, and GABAergic signaling, and explain how these differences are influenced by perinatal and pubertal gonadal hormones. In compiling this research, we outline evidence of what and when sex differences emerge in the developing corticolimbic system, and illustrate how temporal dynamics of its maturational trajectory may differ in male and female rodents. This will help provide insight into potential neural mechanisms underlying sex-specific critical windows for stress susceptibility and behavioral emergence.

Depression is a risk factor for developing Alzheimer\'s disease and Related Dementia (ADRD). We conducted a systematic review between 2008 and October 2018, to evaluate the evidence for a conceptual mechanistic model linking depression and ADRD, focusing on frontal-executive and corticolimbic circuits. We focused on two neuroimaging modalities: diffusion-weighted imaging measuring white matter tract disruptions and resting-state functional MRI measuring alterations in network dynamics in late-life depression (LLD), mild cognitive impairment (MCI), and LLD+MCI vs. healthy control (HC) individuals. Our data synthesis revealed that in some but not all studies, impairment of both frontal-executive and corticolimbic circuits, as well as impairment of global brain topology was present in LLD, MCI, and LLD+MCI vs. HC groups. Further, posterior midline regions (posterior cingulate cortex and precuneus) appeared to have the most structural and functional alterations in all patient groups. Future cohort and longitudinal studies are required to address the heterogeneity of findings, and to clarify which subgroups of people with LLD are at highest risk for developing MCI and ADRD.

The endocannabinoid system (ECS) critically regulates stress responsivity and emotional behavior throughout development. It regulates anxiety-like behaviors in humans and animal models. In addition, it is sensitive to early life stress at the gene expression level in a sex-dependent and region-dependent manner, and these changes are already evident in the adolescent brain. The ECS modulates the neuroendocrine and behavioral effects of stress, and is also capable of being affected by stress exposure itself. Early life stress interferes with the development of corticolimbic circuits, a major location of endocannabinoid receptors, and increases vulnerability to adult psychopathology. Early life stress alters the ontogeny of the ECS, resulting in a sustained deficit in its function, particularly within the hippocampus. Specifically, exposure to early stress results in bidirectional changes in anandamide and 2-AG tissue levels within the amygdala and hippocampus and reduces hippocampal endocannabinoid function at puberty. CB1 receptor densities across all brain regions are downregulated later in life following exposure to early life stress. Manipulations affecting the glucocorticoid and the endocannabinoid systems persistently adjust individual emotional responses and synaptic plasticity. This review aims to show the bidirectional trajectories of endocannabinoid modulation of emotionality in reaction to early life stress.

Being able to limit the pursuit of reward to prevent negative consequences is an important expression of behavioral inhibition. Everyday examples of an inability to exert such control over behavior are the overconsumption of food and drugs of abuse, which are important factors in the development of obesity and addiction, respectively. Here, we use a behavioral task that assesses the ability of male rats to exert behavioral restraint at the mere sight of palatable food during the presentation of an audiovisual threat cue to investigate the corticolimbic underpinnings of behavioral inhibition. We demonstrate a prominent role for the medial prefrontal cortex in the exertion of control over behavior under threat of punishment. Moreover, task engagement relies on function of the ventral striatum, whereas the basolateral amygdala mediates processing of the threat cue. Together, these data show that inhibition of reward pursuit requires the coordinated action of a network of corticolimbic structures.SIGNIFICANCE STATEMENT There is a need for translational models that allow to dissect mechanisms underlying the processes involved in controlling behavior. In this study, we present a novel behavioral task that assesses the ability of rats to exert behavioral restraint over the consumption of a visually present sucrose pellet during the presentation of an audiovisual threat cue. This task requires relatively little behavioral training and it discerns distinct behavioral impairments, including a failure to retrieve stimulus value, a reduced task engagement, and compromised inhibition of behavior. Using pharmacological inactivations of different regions of the corticolimbic system of the rat, we demonstrate dissociable roles for the prefrontal cortex, amygdala, and striatum in inhibition of reward pursuit under threat of punishment.

Amongst a number of negative life sequelae associated with childhood adversity is the later expression of a higher dispositional tendency to experience anger and frustration to a wide range of situations (i.e., trait anger). We recently reported that an association between childhood adversity and trait anger is moderated by individual differences in both threat-related amygdala activity and executive control-related dorsolateral prefrontal cortex (dlPFC) activity, wherein individuals with relatively low amygdala and high dlPFC activity do not express higher trait anger even when having experienced childhood adversity. Here, we examine possible structural correlates of this functional dynamic using diffusion magnetic resonance imaging data from 647 young adult men and women volunteers. Specifically, we tested whether the degree of white matter microstructural integrity as indexed by fractional anisotropy modulated the association between childhood adversity and trait anger. Our analyses revealed that higher microstructural integrity of multiple pathways was associated with an attenuated link between childhood adversity and adult trait anger. Amongst these pathways was the uncinate fasciculus (UF; ΔR 2  = 0.01), which not only provides a major anatomical link between the amygdala and prefrontal cortex but also is associated with individual differences in regulating negative emotion through top-down cognitive reappraisal. These findings suggest that higher microstructural integrity of distributed white matter pathways including but not limited to the UF may represent an anatomical foundation serving to buffer against the expression of childhood adversity as later trait anger, which is itself associated with multiple negative health outcomes.

DNA methylation has been identified as a powerful and activity-dependent regulator of changes in the brain that may underlie neuroadaptations in response to various types of stimuli, including exposure to drugs of abuse. Indeed, the medial prefrontal cortex (mPFC) projections to the nucleus accumbens (NAc) are critically important for reinstated cocaine-seeking in a rodent model of cocaine relapse. This circuitry undergoes several epigenetic modifications following cocaine exposure, including changes in DNA methylation that are associated with drug-seeking behavior. We have previously shown that methyl supplementation via L-Methionine (MET) administration attenuates cocaine-seeking behavior and reverses expression and methylation patterns of the immediate early gene c-fos, suggesting that MET may act by altering the excitability of this circuitry during cocaine reinstatement. In the current study, male rats were microinjected with an adeno-associated virus overexpressing halorhodopsin in the mPFC, optical fibers were surgically implanted into the NAc, and the rats were given injections of MET daily. Rats underwent acquisition of cocaine self-administration (0.75 mg/kg/infusion, 2-h sessions) followed by extinction training in the absence of drug-paired cues. Two reinstatement tests were conducted: cue-induced reinstatement without optogenetic manipulations and cocaine-primed reinstatement with optogenetic inhibition of mPFC-to-NAc projections. There were no group differences before the cocaine-primed reinstatement session, and all groups showed robust cue-induced reinstatement. Both rats treated with MET and rats that received mPFC-to-NAc inhibition showed an abolishment of cocaine-primed reinstatement, suggesting that systemic methyl supplementation may act through this critical circuity.

Major depressive disorder (MDD) affects women approximately twice as often as men. Women are three times as likely to have atypical depression, with hypersomnia and weight gain. This suggests that the molecular mechanisms of MDD may differ by sex.
To test this hypothesis, we performed a large-scale gene expression meta-analysis across three corticolimbic brain regions: the dorsolateral prefrontal cortex, subgenual anterior cingulate cortex, and basolateral amygdala (26 men, 24 women with MDD and sex-matched control subjects). Results were further analyzed using a threshold-free approach, Gene Ontology, and cell type-specific analyses. A separate dataset was used for independent validation (13 MDD subjects/sex and 22 control subjects [13 men, 9 women]).
Of the 706 genes differentially expressed in men with MDD and 882 genes differentially expressed in women with MDD, only 21 were changed in the same direction in both sexes. Notably, 52 genes displayed expression changes in opposite directions between men and women with MDD. Similar results were obtained using a threshold-free approach, in which the overall transcriptional profile of MDD was opposite in men and women. Gene Ontology indicated that men with MDD had decreases in synapse-related genes, whereas women with MDD exhibited transcriptional increases in this pathway. Cell type-specific analysis indicated that men with MDD exhibited increases in oligodendrocyte- and microglia-related genes, while women with MDD had decreases in markers of these cell types.
The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.