Effects of Antiretroviral Treatment on Central and Peripheral Immune Response in Mice with EcoHIV Infection.

HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

Effects of antiretroviral treatment on central and peripheral immune response in mice with EcoHIV infection.

HIV infection is an ongoing global health issue despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F) and tenofovir alafenamide (TAF) on expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.

EcoHIV Infection Modulates the Effects of Cocaine Exposure Pattern and Abstinence on Cocaine Seeking and Neuroimmune Protein Expression in Male Mice.

Cocaine use disorders (CUDs) and human immunodeficiency virus (HIV) remain persistent public health dilemmas throughout the world. One major hurdle for treating CUD is the increase in cocaine craving and seeking behavior that occurs over a protracted period of abstinence, an effect known as the incubation of craving. Little is known about how HIV may modulate this process. Thus, we sought to examine the impact of chronic HIV infection on the incubation of cocaine craving and associated changes in the central and peripheral immune systems. Here, mice were inoculated with EcoHIV, which is a chimeric HIV-1 construct that produces chronic HIV infection in mice. EcoHIV- and sham-infected mice were conditioned with cocaine daily or intermittently in a conditioned place preference (CPP) paradigm, followed by 1 or 21 days of forced abstinence prior to assessing preference for the cocaine-paired chamber. Under both conditioning regimens, sham mice exhibited incubation of cocaine CPP after 21 days of abstinence. EcoHIV-infected mice conditioned daily with cocaine showed enhanced cocaine seeking at both abstinence timepoints, whereas infected mice conditioned intermittently showed a reversal of the incubation effect, with higher cocaine seeking after 1 day of abstinence compared to 21 days. Analysis of corticolimbic CX3CL1-CX3CR1 and glutamate receptor expression revealed alterations in medial prefrontal cortex (mPFC) CX3CL1 and nucleus accumbens (NAc) GluN2A receptors that correlated with cocaine seeking following daily cocaine exposure. Moreover, examination of peripheral immune markers showed that the effect of abstinence and EcoHIV infection on these measures depended on the cocaine exposure regimen. Altogether, these results highlight the importance of cocaine abstinence and exposure pattern as critical variables that modulate HIV-associated neuroimmune outcomes and relapse vulnerability.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between HIV infection and cocaine use disorder is likely bidirectional, with cocaine use directly impacting immune function while HIV infection alters addiction-related behavior. To better characterize the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilizes a humanized mouse model to investigate the outcomes of HIV-1 infection on cocaine-related behaviors in a conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection selectively impairs cocaine CPP extinction without effecting reinstatement or cocaine seeking under conflict. Behavioral alterations are accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes are observed in human cytokines, including HIV-induced reductions in human TNFα, and cocaine and HIV interactions on GM-CSF levels. Together these data provide new insights into the unique neurobehavioral outcomes of HIV infection and cocaine exposure and how they interact to effect immune responses.

Sex and individual differences in the effect of chronic low-dose ethanol on behavioral strategy selection.

BACKGROUND: The development of an alcohol use disorder (AUD) involves impaired behavioral control and flexibility. Behavioral inflexibility includes an inability to shift behavior in response to changes in behavioral outcomes. Low levels of ethanol drinking may promote the formation of inflexible, habitual reward seeking, but this may depend on the timing of ethanol exposure in relation to learning. The goal of this study was to determine whether a history of low-dose ethanol exposure promoted contingency-insensitive sucrose seeking and altered behavioral strategy selection. METHODS: Male and female C57BL/6J mice were trained to perform a response (lever press) for sucrose on two different reinforcement schedules: one that is thought to promote inflexible responding (random interval) and one that maintains flexible responding (variable ratio [VR]). Following instrumental training each day, mice were exposed to saline or low-dose ethanol (0.5 g/kg; i.p.) either proximal (1 h after) or distal (4 h after) to learning. Mice were then tested for sensitivity to changes in contingency in a contingency degradation test. RESULTS: A history of low-dose ethanol exposure shifted behavioral strategy selection, as measured by reward tracking behavior, but this depended on sex and reinforcement schedule history. Both male and female mice used different strategies depending on the reinforcement schedule, but only males exhibited ethanol-induced shifts in strategy selection. A history of low-dose ethanol exposure did not impact contingency sensitivity in males but promoted insensitivity in females specifically on the VR lever. CONCLUSIONS: Female mice show distinct behavioral effects of repeated, low-dose ethanol exposure as compared to males, with sex differences in the use of reward tracking strategies to guide behavior. Future studies should investigate sex differences in the neural consequences of chronic low-dose ethanol exposure that may underlie behavioral changes.

Positive correlation between measures of habitual responding and motivated responding in mice.

Habit and motivation are thought to be separate processes, with motivated behavior often considered to be goal directed, whereas habits are defined by the absence of goal-directed control over behavior. However, there has been increasing interrogation of the binary nature of habitual versus goal-directed behavior. Furthermore, although drug and alcohol exposure can promote the formation of habits, drug seeking itself can also be highly flexible, pointing toward the need for complex consideration of the parallel processes that drive behavior. The goal of the current study was to determine whether there was a relation between motivation-as measured by progressive ratio-and habit-as measured by contingency degradation-and whether this relation was affected by ethanol exposure history and sex. The results showed that these measures were positively correlated such that greater contingency insensitivity was associated with achieving higher break points on the progressive-ratio task. However, this relation depended on reinforcement schedule history, ethanol exposure history, and sex. These point to potential relations between measures of habit and motivation and stress the importance of carefully parsing behavioral findings and assays. These findings are also expected to inform future substance use research, as drug history may affect these relations.

Impaired extinction of cocaine seeking in HIV-infected mice is accompanied by peripheral and central immune dysregulation.

Substance use disorders (SUDs) are highly comorbid with HIV infection, necessitating an understanding of the interactive effects of drug exposure and HIV. The relationship between progressive HIV infection and cocaine use disorder is likely bidirectional, with cocaine use having direct effects on immune function while HIV infection can alter addiction-related behavior. To better characterized the neurobehavioral and immune consequences of HIV infection and cocaine exposure, this study utilized a humanized mouse model to investigate the outcomes of progressive HIV infection on cocaine-related behaviors in a cocaine conditioned place preference (CPP) model, and the interactive effects of cocaine and HIV infection on peripheral and central nervous system inflammation. HIV infection did not impact the formation of a cocaine CPP, but did result in resistance to extinction of the CPP. No effects of HIV on yohimbine-primed reinstatement or cocaine seeking under conflict were observed. These behavioral alterations were accompanied by immune changes in HIV infected mice, including increased prefrontal cortex astrocyte immunoreactivity and brain-region specific effects on microglia number and reactivity. Peripheral immune system changes were observed in both mouse and human markers. Among other targets, this included HIV-induced reductions in mouse IL-1α and G-CSF and human TNFα and cocaine-induced alterations in human TNFα and mouse GM-CSF such that cocaine exposure increases both cytokines only in the absence of HIV infection. Together these data provide new insights into the unique neurobehavioral processes underlying HIV infection and cocaine use disorders, and further how they interact to effect immune responses.

Advancing the preclinical study of comorbid neuroHIV and substance use disorders: Current perspectives and future directions.

Human immunodeficiency virus (HIV) remains a persistent public health concern throughout the world. Substance use disorders (SUDs) are a common comorbidity that can worsen treatment outcomes for people living with HIV. The relationship between HIV infection and SUD outcomes is likely bidirectional, making clear interrogation of neurobehavioral outcomes challenging in clinical populations. Importantly, the mechanisms through which HIV and addictive drugs disrupt homeostatic immune and CNS function appear to be highly overlapping and synergistic within HIV-susceptible reward and motivation circuitry in the central nervous system. Decades of animal research have revealed invaluable insights into mechanisms underlying the pathophysiology SUDs and HIV, although translational studies examining comorbid SUDs and HIV are very limited due to the technical challenges of modeling HIV infection preclinically. In this review, we discuss preclinical animal models of HIV and highlight key pathophysiological characteristics of each model, with a particular emphasis on rodent models of HIV. We then review the implementation of these models in preclinical SUD research and identify key gaps in knowledge in the field. Finally, we discuss how cutting-edge behavioral neuroscience tools, which have revealed key insights into the neurobehavioral mechanisms of SUDs, can be applied to preclinical animal models of HIV to reveal potential, novel treatment avenues for comorbid HIV and SUDs. Here, we argue that future preclinical SUD research would benefit from incorporating comorbidities such as HIV into animal models and would facilitate the discovery of more refined, subpopulation-specific mechanisms and effective SUD prevention and treatment targets.

Effects of adolescent ethanol exposure on adult nondrug reward seeking behavior in male and female mice.

BACKGROUND: Adolescent alcohol use is associated with an increased likelihood of developing an alcohol use disorder in adulthood, potentially due to the effects of alcohol exposure on reward-seeking behavior. However, it remains unclear whether adolescent drinking is sufficient to alter nondrug reward seeking in adulthood. As adolescence is a period of both brain and sexual maturation, which occur in a sex-dependent manner, males and females may be differentially sensitive to the consequences of adolescent alcohol exposure. The present study investigated whether adolescent ethanol exposure affected food reward taking and seeking in male and female adult mice. METHODS: Male and female C57BL/6J mice underwent intermittent ethanol exposure (AIE) via vapor inhalation during early adolescence (28-42 days of age). At 10 weeks of age, the mice were trained in a conditioned place preference paradigm (CPP) for a food reward. We measured food consumption, CPP, and cFos expression in multiple brain regions following CPP testing. Data were analyzed using repeated measures analysis of variance with exposure (air vs. AIE), sex, and time as factors. RESULTS: AIE exposure increased food consumption during CPP training in adult male mice, but reduced pellet consumption in adult female mice. AIE exposure impaired CPP expression only in female mice. Despite these behavioral differences, exposure to the reward-paired chamber did not induce differential cFos expression following CPP testing in the prelimbic and infralimbic cortices or the nucleus accumbens core and shell. CONCLUSION: These findings indicate that adolescent ethanol exposure disrupted nondrug reward taking and seeking in adulthood in female mice and altered consumption in adult male mice.

A History of Low-Dose Ethanol Shifts the Role of Ventral Hippocampus during Reward Seeking in Male Mice.

Although casual drinkers are a majority of the alcohol drinking population, understanding of the long-term effects of chronic exposure to lower levels of alcohol is limited. Chronic exposure to lower doses of ethanol may facilitate the development of alcohol use disorders, potentially because of ethanol effects on reward learning and motivation. Indeed, our previously published findings showed that chronic low-dose ethanol exposure enhanced motivation for sucrose in male, but not female, mice. As the ventral hippocampus (vHPC) is sensitive to disruption by higher doses of chronic ethanol and tracks reward-related information, we hypothesized that this region is impacted by low-dose ethanol and, further, that manipulating vHPC activity would alter reward motivation. In vivo electrophysiological recordings of vHPC population neural activity during progressive ratio testing revealed that vHPC activity was suppressed in the period immediately after reward seeking (lever press) in ethanol-naive controls, whereas suppression of vHPC activity anticipated reward seeking in ethanol-exposed mice. In both ethanol-naive and exposed mice, vHPC activity was suppressed before a reward magazine entry. Temporally selective inhibition of vHPC using optogenetics increased motivation for sucrose in ethanol-naive controls, but not in ethanol-exposed mice. Further, regardless of exposure history, vHPC inhibition promoted checking of the reward magazine, indicating a role for vHPC in reward tracking. There was no effect of chemogenetic inhibition of the vHPC either during training or testing on sucrose reward motivation. These results reveal novel ethanol-induced alterations in vHPC neural activity that shift how vHPC activity is able to regulate reward seeking.

Effects of ethanol on mechanical allodynia and dynamic weight bearing in male and female mice with spared nerve injury.

BACKGROUND: Men and women with chronic pain report increased alcohol use and are more likely to be diagnosed with alcohol use disorder. The relationship between alcohol use and pain is bidirectional. Alcohol is used as an analgesic, but chronic alcohol intake increases pain. Sex differences in the relationship between chronic pain and alcohol are reported in the clinical and preclinical literature, but due to this bidirectional relationship, it is challenging to investigate the mechanisms that contribute to these differences. Thus, animal models of chronic pain are needed to characterize the efficacy of ethanol as an analgesic in males and females. The current experiments tested the hypothesis that ethanol differentially reduces pain behaviors in male and female mice in chronic neuropathic pain. METHODS: The spared nerve injury (SNI) model was used to investigate the analgesic effects of multiple doses of ethanol (0.5, 1, 2, g/kg i.p.) in male and female mice using von Frey and dynamic weight-bearing (DWB) assays. RESULTS: In both male and female mice, SNI led to robust allodynia and shifts in dynamic weight bearing. In male SNI mice, all three doses of ethanol fully reversed mechanical allodynia and shifts in DWB. In SNI females, only the highest dose (2.0 g/kg) was fully antiallodynic in the von Frey assay, while shifts in weight bearing were reversed at the 1.0 and 2.0 g/kg doses. The differences between male and females were not due to lower blood ethanol concentrations in female mice. CONCLUSION: These data indicate that while ethanol has antiallodynic and antinociceptive effects in male and female mice, the doses and time course of these effects are distinct. Studies investigating the relationship between pain and ethanol exposure in mice should consider sex as a key variable. These data also inform reported sex differences in rodent models of chronic pain and in chronic pain patients.

Estrous cycle and hormone regulation of stress-induced reinstatement of reward seeking in female mice.

Women are more vulnerable to stress-induced craving, which may be associated with increased vulnerability to relapse. Susceptibility to stress-induced craving also appears to be modulated by the menstrual cycle and is negatively correlated with circulating progesterone levels in women. However, the factors that contribute to relapse vulnerability are poorly characterized in female animals. In this study, we assessed whether chronic ethanol exposure, estrous cycle, or exogenous progesterone administration modulated vulnerability to stress-induced reinstatement. To model ethanol dependence, adult female C57Bl/6J mice underwent chronic intermittent ethanol (CIE) exposure via vapor inhalation. Seventy-two hours after the final ethanol exposure, food-restricted mice began training in a conditioned place preference paradigm (CPP) for a food reward, followed by extinction training. Mice were then subjected to forced swim stress and assessed for reinstatement of their preference for the reward-paired chamber. CIE did not affect stress-induced reinstatement. However, stress-induced reinstatement was attenuated during the diestrus phase, when endogenous levels of progesterone peak in female mice. Further, administration of exogenous progesterone mimicked the attenuated reinstatement observed in diestrus. These findings indicate that circulating hormone levels modulate susceptibility to relapse-like behaviors and implicate progesterone as a potential target for treating stress-induced relapse in women.

Sex-related differences in pattern of ethanol drinking under the intermittent-access model and its impact on exploratory and anxiety-like behavior in Long-Evans rats.

BACKGROUND: While men in the United States consume more alcohol than women, rates of drinking are converging. Nevertheless, females remain underrepresented in preclinical alcohol research. Here, we examined rats' sex-related differences in patterns of ethanol (EtOH) drinking and the effects of this drinking on exploratory and anxiety-like behavior. METHODS: Adult male and female Long-Evans rats were given 20% ethanol under the intermittent-access two-bottle-choice paradigm. Their intake was measured daily for the first 7 weeks. During the eighth week, intake was measured over the 24 h of daily access. During the ninth week, they, along with EtOH-naive controls, were tested prior to daily access in a novel chamber, light-dark box, and hole board apparatus. During the tenth week, blood ethanol concentration (BEC) was assessed after 30 to 40 min of access. RESULTS: Females overall demonstrated higher ethanol intake and preference across all access weeks than males, although only half of females drank significantly more than males. Across 24 h of daily access, both sexes had their highest intake in the first 30 min and their lowest in the middle of the light phase of the light/dark cycle. Despite their greater ethanol intake, females did not show significantly different BECs than males. In behavioral tests, females showed less vertical time in a novel activity chamber, more movement between chambers in a light-dark box, and more nose pokes in a hole-board apparatus than males. While a history of ethanol drinking led to a trend for lower vertical time in the activity chamber and greater chamber entries in the light-dark box, the effects were not sex-dependent. CONCLUSIONS: These results suggest that female and male rats could both be tested for acute effects of ethanol after 30 min of daily access, but that nuanced considerations are needed in the design of these experiments and the interpretation of their findings.

Reinforcement History Dependent Effects of Low Dose Ethanol on Reward Motivation in Male and Female Mice.

Alcohol use disorders (AUDs) are more prevalent in men than in women, though AUD diagnoses in women are growing rapidly, making an understanding of sex differences in alcohol-related behaviors increasingly important. The development of AUDs involves the transition from casual, low levels of alcohol drinking to higher, maladaptive levels. The ability of low dose alcohol to drive reward and drug seeking may differ in males and females, and this could underlie differences in susceptibility to AUD. In this study we sought to determine whether a history of chronic, low dose ethanol exposure (0.5 g/kg; i.p.) could drive sucrose reward seeking and motivation, and whether this differed between male and female mice. Adult mice were trained to lever press for a liquid sucrose reward on two reinforcement schedules: a random interval (RI) schedule and a variable ratio (VR) schedule. After training, mice were tested on each of these levers for reward motivation using a progressive ratio test. We found that a history of low dose ethanol exposure increased sucrose reward motivation in male mice, but only on the RI lever and only when exposure occurred proximal to learning. Female mice were more motivated for sucrose on the RI lever than the VR lever regardless of ethanol exposure condition. These findings indicate that training on different reinforcement schedules affects reward motivation. Further, we show that males are more susceptible to the effects of low dose ethanol on sucrose reward motivation than females. These data broaden our understanding of sex differences in reward seeking as a result of ethanol exposure.

Brain region-dependent alterations in polysialic acid immunoreactivity across the estrous cycle in mice.

N-glycosylation is a posttranslational modification that plays significant roles in regulating protein function. One form of N-glycosylation, polysialylation, has been implicated in many processes including learning and memory, addiction, and neurodegenerative disease. Polysialylation appears to be modulated by the estrous cycle in the hypothalamus in rat, but this has not been assessed in other brain regions. To determine if polysialylation was similarly estrous phase-dependent in other neuroanatomical structures, the percent area of polysialic acid (PSA) immunoreactivity in subregions of the medial prefrontal cortex, hippocampus, and nucleus accumbens was assessed in each of the four phases in adult female mice. In this study, we found that PSA immunoreactivity fluctuated across the estrous cycle in a subregion-specific manner. In the prefrontal cortex, PSA immunoreactivity was significantly lower in proestrus phase compared to estrus in the prelimbic cortex, but did not differ across the estrous cycle in the infralimbic cortex. In the hippocampus, PSA immunoreactivity was significantly increased in proestrus compared to metestrus in the CA1 and CA2 and compared to diestrus in CA3, but remain unchanged in the dentate gyrus. PSA immunoreactivity did not vary across the estrous cycle in the nucleus accumbens core or shell. These findings may have implications for estrous cycle-dependent alterations in behavior.

Astrocyte modulation of extinction impairments in ethanol-dependent female mice.

Rates of alcohol use disorders are increasing in women, and there is growing evidence that both the cognitive and biological consequences of alcohol dependence are distinct in women as compared to men. Despite this, the neurobehavioral outcomes of chronic alcohol exposure are poorly characterized in women and female animals. In this study, we find that ethanol dependence impaired extinction of reward seeking in a food conditioned place preference task in female mice. At the same time point, ethanol-dependent females exhibited astrocytic dysregulation as indicated by a brain region-specific reduction in glial fibrillary acidic protein (GFAP) expression. Using a chemogenetic strategy, we demonstrate that modulating astrocyte function via chemogenetic activation of Gq-signaling in nucleus accumbens astrocytes transiently rescued extinction in ethanol-dependent females without impacting basal reward seeking. These findings identify astrocyte function as a potential target for the restoration of behavioral flexibility following chronic alcohol exposure in females.

Selective Deficits in Contingency-Driven Ethanol Seeking Following Chronic Ethanol Exposure in Male Mice.

BACKGROUND: People with alcohol use disorders exhibit an overreliance on habitual response strategies which may result from a history of chronic alcohol exposure. Although habits are defined by behavior that persists despite changes in outcome value and in action-outcome relationships, most research investigating the effects of ethanol exposure on habits has focused only on outcome devaluation. A clear understanding of the effects of chronic alcohol exposure on the ability to flexibly update behavior may provide insight into the behavioral deficits that characterize alcohol use disorders. METHODS: To dissociate the effects of chronic intermittent ethanol (CIE) exposure on contingency-mediated sucrose versus ethanol seeking, adult male C57Bl/6J mice were assigned to 2 separate experiments. In the first experiment, mice were trained to self-administer ethanol prior to 2 cycles of interleaved CIE exposure by vapor inhalation. In a second experiment, mice were trained to self-administer sucrose and ethanol in separate training sessions prior to 4 cycles of interleaved CIE. The use of contingencies to mediate reward seeking was assessed using a contingency degradation paradigm. RESULTS: In mice trained to self-administer only ethanol, 2 weeks of CIE resulted in escalated self-administration. At this time point, CIE-exposed mice, but not air-exposed controls, exhibited ethanol seeking that was insensitive to changes in action-outcome contingency, consistent with habitual ethanol seeking. In mice trained to self-administer ethanol and sucrose rewards in sequential sessions, no escalation in self-administration across 4 weeks of CIE was observed. Under these conditions, neither Air- nor CIE-exposed mice reduced ethanol seeking in response to contingency degradation. In contrast, sucrose seeking remained goal-directed. CONCLUSIONS: Our results suggest that chronic ethanol exposure impairs contingency-driven ethanol seeking more readily than sucrose-seeking behavior. Further, these findings indicate that the transition from contingency-mediated ethanol seeking occurs more rapidly than for sucrose seeking under similar ethanol exposure conditions.

Arbitration of Approach-Avoidance Conflict by Ventral Hippocampus.

When environmental cues or stimuli that represent both rewarding and aversive outcomes are presented, complex computations must be made in order to determine whether approach or avoidance is the better behavioral strategy. In many neuropsychiatric illnesses these computations can be skewed. In some instances, circumstances that may normally warrant avoidance instead promote approach, thus producing compulsive-like behavioral strategies that are inflexible in response to new or conflicting information. Alternatively, high sensitivity to aversion or low sensitivity to reward can result in the failure to achieve goals and loss of resilience that characterizes depressive disorders. Increases in compulsive-like behavior have been found to be associated with disrupted signaling in regions that regulate response to conflicting stimuli, including the hippocampus. Classic behavioral inhibition theories of hippocampus function in anxiety suggest that the hippocampus blocks aberrant behavior in response to anxiety related cues or stimuli. The hippocampus may act to block approach in the face of conflicting stimuli. Dysregulations of hippocampal function, as may be present in neuropsychiatric disorders, may therefore promote aberrant approach behavior. The ventral hippocampus (vHPC) subregion is key for coordinating this approach/avoidance conflict resolution, likely through its participation with cortico-striatal and mesolimbic circuits. We revisit Gray's behavioral inhibition theory of HPC function, first posited in the 1980s, and interpret in the context of new knowledge on vHPC function gained through modern technology. Taken together with the extant, classical literature on hippocampal function, we propose that these new findings suggest that vHPC circuits balance behavioral response to conflicting stimuli in a manner that is both state- and context-dependent and, further, that disruption of specific vHPC circuits tips the balance in favor of biased approach or avoidance behavioral strategies.

Comorbid HIV infection and alcohol use disorders: Converging glutamatergic and dopaminergic mechanisms underlying neurocognitive dysfunction.

Alcohol use disorders (AUDs) are highly comorbid with human immunodeficiency virus (HIV) infection, occurring at nearly twice the rate in HIV positive individuals as in the general population. Individuals with HIV who consume alcohol show worse long-term prognoses and may be at elevated risk for the development of HIV-associated neurocognitive disorders. The direction of this relationship is unclear, and likely multifactorial. Chronic alcohol exposure and HIV infection independently promote cognitive dysfunction and further may interact to exacerbate neurocognitive deficits through effects on common targets, including corticostriatal glutamate and dopamine neurotransmission. Additionally, drug and alcohol use is likely to reduce treatment adherence, potentially resulting in accelerated disease progression and subsequent neurocognitive impairment. The development of neurocognitive impairments may further reduce cognitive control over behavior, resulting in escalating alcohol use. This review will examine the complex relationship between HIV infection and alcohol use, highlighting impacts on dopamine and glutamate systems by which alcohol use and HIV act independently and in tandem to alter corticostriatal circuit structure and function to dysregulate cognitive function.

Sex Differences in Ethanol Reward Seeking Under Conflict in Mice.

BACKGROUND: Alcohol use disorders are characterized by inflexible alcohol seeking that occurs despite adverse consequences. Males and females are differentially sensitive to ethanol (EtOH) reward, but it is unclear whether sex differences in EtOH seeking under reward-aversion conflict are present. METHODS: To investigate sex differences in EtOH seeking under conflict, adult male and female C57BL/6J mice underwent chronic intermittent EtOH (CIE) exposure by vapor inhalation or served as air-exposed controls. After CIE, mice were trained in a modified EtOH conditioned place preference paradigm. During 3 conditioning sessions, 2 g/kg EtOH was administered prior to confinement in the "EtOH-paired" chamber. On alternating days, saline was injected prior to confinement in the "saline-paired" chamber. After conditioning, mice experienced a footshock in the EtOH-paired chamber. EtOH-seeking behavior was assessed before and after footshock. RESULTS: Control and CIE-exposed males reduced the time spent in and increased latency to enter the reward-paired chamber following footshock. Control females did not alter EtOH-seeking behavior following footshock. CIE-exposed females spent more time in the EtOH-paired chamber at baseline. However, following a footshock, CIE-exposed females significantly reduced the time spent in and increased latency to enter the EtOH-paired chamber. CONCLUSIONS: Nondependent female mice exhibited aversion-resistant alcohol seeking to a greater degree than males. Chronic EtOH exposure did not impact EtOH seeking in males. In females, CIE enhanced EtOH seeking in the absence of conflict, but reduced EtOH seeking after an aversive experience. While these sex-specific effects of CIE are not present when reward seeking is assessed in the absence of an aversive experience, multiple factors may underlie the differences in reward seeking despite adverse consequences, including reward- and aversion-related learning and decision making under conflict. These data highlight the importance of considering sex as a variable influencing EtOH seeking and provide a greater understanding of how sex interacts with EtOH exposure to alter behavior.