Chandni Sheth

Lesions of the lateral habenula increase voluntary ethanol consumption and operant self-administration, block yohimbine-induced reinstatement of ethanol seeking, and attenuate ethanol-induced conditioned taste aversion

The lateral habenula (LHb) plays an important role in learning driven by negative outcomes. Many drugs of abuse, including ethanol, have dose-dependent aversive effects that act to limit intake of the drug. However, the role of the LHb in regulating ethanol intake is unknown. In the present study, we compared voluntary ethanol consumption and self-administration, yohimbine-induced reinstatement of ethanol seeking, and ethanol-induced conditioned taste aversion in rats with sham or LHb lesions. In rats given home cage access to 20% ethanol in an intermittent access two bottle choice paradigm, lesioned animals escalated their voluntary ethanol consumption more rapidly than sham-lesioned control animals and maintained higher stable rates of voluntary ethanol intake. Similarly, lesioned animals exhibited higher rates of responding for ethanol in operant self-administration sessions. In addition, LHb lesion blocked yohimbine-induced reinstatement of ethanol seeking after extinction. Finally, LHb lesion significantly attenuated an ethanol-induced conditioned taste aversion. Our results demonstrate an important role for the LHb in multiple facets of ethanol-directed behavior, and further suggest that the LHb may contribute to ethanol-directed behaviors by mediating learning driven by the aversive effects of the drug.

The lateral hypothalamus to lateral habenula projection, but not the ventral pallidum to lateral habenula projection, regulates voluntary ethanol consumption

Graphical abstract Figure. No Caption available. HighlightsLesioning the stria medullaris increases voluntary ethanol consumption.Disconnection of the lateral hypothalamus to lateral habenula projection increases voluntary ethanol consumption.Disconnection of the ventral pallidum to lateral habenula projection does not alter ethanol‐directed behaviors. ABSTRACT The lateral habenula (LHb) is an epithalamic brain region implicated in aversive processing via negative modulation of midbrain dopamine (DA) and serotonin (5‐HT) systems. Given the role of the LHb in inhibiting DA and 5‐HT systems, it is thought to be involved in various psychiatric pathologies, including drug addiction. In support, it has been shown that LHb plays a critical role in cocaine‐ and ethanol‐related behaviors, most likely by mediating drug‐induced aversive conditioning. In our previous work, we showed that LHb lesions increased voluntary ethanol consumption and operant ethanol self‐administration and blocked yohimbine‐induced reinstatement of ethanol self‐administration. LHb lesions also attenuated ethanol‐induced conditioned taste aversion suggesting that a mechanism for the increased intake of ethanol may be reduced aversion learning. However, whether afferents to the LHb are required for mediating effects of the LHb on these behaviors remained to be investigated. Our present results show that lesioning the fiber bundle carrying afferent inputs to the LHb, the stria medullaris (SM), increases voluntary ethanol consumption, suggesting that afferent structures projecting to the LHb are important for mediating ethanol‐directed behaviors. We then chose two afferent structures as the focus of our investigation. We specifically studied the role of the inputs from the lateral hypothalamus (LH) and ventral pallidum (VP) to the LHb in ethanol‐directed behaviors. Our results show that the LH‐LHb projection is necessary for regulating voluntary ethanol consumption. These results are an important first step towards understanding the functional role of afferents to LHb with regard to ethanol consumption.

Lesion of the rostromedial tegmental nucleus increases voluntary ethanol consumption and accelerates extinction of ethanol-induced conditioned taste aversion

RationaleEthanol has rewarding and aversive properties, and the balance of these properties influences voluntary ethanol consumption. Preclinical and clinical evidence show that the aversive properties of ethanol limit intake. The neural circuits underlying ethanol-induced aversion learning are not fully understood. We have previously shown that the lateral habenula (LHb), a region critical for aversive conditioning, plays an important role in ethanol-directed behaviors. However, the neurocircuitry through which LHb exerts its actions is unknown.ObjectiveIn the present study, we investigate a role for the rostromedial tegmental nucleus (RMTg), a major LHb projection target, in regulating ethanol-directed behaviors.MethodsRats received either sham or RMTg lesions and were studied during voluntary ethanol consumption; operant ethanol self-administration, extinction, and yohimbine-induced reinstatement of ethanol-seeking; and ethanol-induced conditioned taste aversion (CTA).ResultsRMTg lesions increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA.ConclusionsThe RMTg plays an important role in regulating voluntary ethanol consumption, possibly by mediating ethanol-induced aversive conditioning.

Increased anxiety and anhedonia in female rats following exposure to altitude

Sheth, Chandni, Hendrik Ombach, Paul Olson, Perry F. Renshaw, and Shami Kanekar. Increased anxiety and anhedonia in female rats following exposure to altitude. High Alt Med Biol. 19:81-90, 2018.-Anxiety disorders are chronic, highly prevalent conditions, often comorbid with depression. Both anxiety and depression form major risk factors for suicide. Living at altitude is associated with higher rates of depression and suicide, leading us to address whether anxiety disorders may also be amplified at altitude. Using a novel translational animal model, we previously showed that depression-like behavior increases with altitude of housing in female, but not male rats. We now use this model to examine the effects of altitude on both anxiety-like behavior and anhedonia, a core symptom of depression. After housing for a week at sea level, 4500 or 10,000 ft, rats were evaluated for anxiety in the open-field test or the elevated plus maze, and anhedonia in the sucrose preference test. Another group was tested at baseline. Anxiety-like behavior increased in females housed at altitude. In females, lower sucrose preference was seen in those housed at 10,000 ft versus those at sea level. Males showed no change in anxiety or anhedonia across groups. These data suggest that living at moderate-high altitude may pose a risk factor for those vulnerable to anxiety disorders, with the potential to be particularly detrimental to females at altitude.

Altered Cortical Gamma-Amino Butyric Acid in Female Veterans With Suicidal Behavior: Sex Differences and Clinical Correlates:

Background Suicide is a public health concern in the civilian and veteran populations. Stressful life events are precipitating factors for suicide. The neurochemical underpinnings of the association between stress/trauma and suicide risk are unclear, especially with regard to sex differences. We hypothesized that gamma-amino butyric acid (GABA), the major inhibitory neurotransmitter, may be a neurochemical candidate that is critical in the association between stress and suicide risk in veterans. Methods Proton magnetic resonance spectroscopy at 3.0 Tesla was used to measure in vivo neurochemistry in the anterior cingulate cortex (predominantly the dorsal anterior cingulate cortex) of 81 veterans (16 females), including 57 (11 females) who endorsed past suicidal ideation and/or suicide attempt and 24 (5 females) with no history of suicidal ideation and/or suicide attempt. Suicidal behavior (SB) was defined as the presence of suicidal ideation and/or suicide attempt. Results We observed no significant differences in GABA/creatine + phosphocreatine (Cr + PCr) between veterans with SB (SB+) and without SB (SB−). However, the female SB+ group showed significantly reduced GABA/Cr + PCr versus the female SB− group. We observed a trend-level significant negative correlation between GABA/Cr + PCr and the Defensive Avoidance subscale on the Trauma Symptom Inventory in the SB+ group. In contrast, the SB− group exhibited a positive relationship between the two variables. Furthermore, we found significant negative correlations between GABA/Cr + PCr and Hamilton Rating Scale for Depression scores as well as between GABA/Cr + PCr and several subscales of the Trauma Symptom Inventory in female veterans. Conclusions This study suggests that reduced GABA/Cr + PCr ratio in the anterior cingulate cortex, which may be related to altered inhibitory capacity, may underlie suicide risk in female veterans. Further, the negative association between GABA/Cr + PCr and stress symptomatology and depression scores suggests that magnetic resonance spectroscopy studies may shed light on intermediate phenotypes of SB.

Chronic Stress in Adolescents and Its Neurobiological and Psychopathological Consequences: An RDoC Perspective:

The Research Domain Criteria (RDoC) initiative provides a strategy for classifying psychopathology based on behavioral dimensions and neurobiological measures. Neurodevelopment is an orthogonal dimension in the current RDoC framework; however, it has not yet been fully incorporated into the RDoC approach. A combination of both a neurodevelopmental and RDoC approach offers a multidimensional perspective for understanding the emergence of psychopathology during development. Environmental influence (e.g., stress) has a profound impact on the risk for development of psychiatric illnesses. It has been shown that chronic stress interacts with the developing brain, producing significant changes in neural circuits that eventually increase the susceptibility for development of psychiatric disorders. This review highlights effects of chronic stress on the adolescent brain, as adolescence is a period characterized by a combination of significant brain alterations, high levels of stress, and emergence of psychopathology. The literature synthesized in this review suggests that chronic stress-induced changes in neurobiology and behavioral constructs underlie the shared vulnerability across a number of disorders in adolescence. The review particularly focuses on depression and substance use disorders; however, a similar argument can also be made for other psychopathologies, including anxiety disorders. The summarized findings underscore the need for a framework to integrate neurobiological findings from disparate psychiatric disorders and to target transdiagnostic mechanisms across disorders.

Hypobaric hypoxia exposure in rats differentially alters antidepressant efficacy of the selective serotonin reuptake inhibitors fluoxetine, paroxetine, escitalopram and sertraline

ABSTRACT Treatment‐resistant depression, a chronic condition that affects 30% of depressed patients on antidepressants, is highly linked to suicidal behavior. Chronic hypoxia exposure via living at altitude (hypobaric hypoxia) or with chronic hypoxic diseases is demographically linked to increased risk for depression and suicide. We previously demonstrated that housing rats at altitude for a week incrementally increases depression‐like behavior in the forced swim test (FST) in females, but not males. In animal models, high altitude exposure reduces brain serotonin, and selective serotonin reuptake inhibitors (SSRIs) can lose efficacy when brain serotonin levels are low. To address whether residence at moderate altitude is detrimental to SSRI function, we examined SSRI efficacy in the FST after a week of housing rats at altitudes of 4500 ft. or 10,000 ft. as compared to at sea level. In females, the tricyclic antidepressant desipramine (positive control) functioned well in all groups, increasing latency to immobility and decreasing immobility, by increasing climbing. However, the SSRIs fluoxetine, paroxetine and escitalopram were ineffective in females in all groups: only paroxetine improved swimming in the FST as expected of a SSRI, while all three unexpectedly reduced climbing. Fluoxetine was also ineffective in male rats. Sertraline was the only SSRI with antidepressant efficacy at altitude in both females and males, increasing swimming, climbing and latency to immobility, and reducing immobility. Hypobaric hypoxia thus appears to be detrimental to efficacy of the SSRIs fluoxetine, paroxetine and escitalopram, but not of sertraline. Unlike the other SSRIs, sertraline can improve both serotonergic and dopaminergic transmission, and may be less impacted by a hypoxia‐induced serotonin deficit. A targeted approach may thus be necessary for successful antidepressant treatment in patients with depression who live at altitude or with chronic hypoxic diseases, and that sertraline may be the SSRI of choice for prescription for this population. HighlightsTreatment‐resistant depression is highly linked to suicidal behavior.Living at altitude (in hypobaric hypoxia) is linked to high MDD and suicide rates.In a rodent model, depression‐like behavior increases with altitude of housing.We therefore studied SSRI efficacy in a rodent model of hypobaric hypoxia.Prozac®, Paxil® and Lexapro® lose efficacy at altitude, but Zoloft® does not.Zoloft® (sertraline) may thus be the SSRI of choice for MDD in chronic hypoxia.