Sex differences in hippocampal cognition and neurogenesis.

The generalization of fear memories is an adaptive neurobiological process that promotes survival in complex and dynamic environments. When confronted with a potential threat, an animal must select an appropriate defensive response based on previous experiences that are not identical, weighing cues and contextual information that may predict safety or danger. Like other aspects of fear memory, generalization is mediated by the coordinated actions of prefrontal, hippocampal, amygdalar, and thalamic brain areas. In this review article, we describe the current understanding of the behavioral, neural, genetic, and biochemical mechanisms involved in the generalization of fear. Fear generalization is a hallmark of many anxiety and stress-related disorders, and its emergence, severity, and manifestation are sex-dependent. Therefore, to improve the dialog between human and animal studies as well as to accelerate the development of effective therapeutics, we emphasize the need to examine both sex differences and remote timescales in rodent models.

The neurobiology of fear generalization

Epidemiological sex differences in anxiety disorders and major depression are well characterized. Yet the circuits and mechanisms that contribute to these differences are understudied, because preclinical studies have historically excluded female rodents. This oversight is beginning to be addressed, and recent studies that include male and female rodents are identifying sex differences in neurobiological processes that underlie features of these disorders, including conflict anxiety, fear processing, arousal, social avoidance, learned helplessness and anhedonia. These findings allow us to conceptualize various types of sex differences in the brain, which in turn have broader implications for considering sex as a biological variable. Importantly, comparing the sexes could aid in the discovery of novel therapeutics. Male-only studies predominate preclinical research on anxiety and depression. In this Review, Bangasser and Cuarenta discuss how, since the inclusion of female subjects, new mechanisms have been identified that underlie vulnerability to these disorders, and that reveal novel targets for treatments.

Sex differences in anxiety and depression: circuits and mechanisms.

Know safety, no fear.

Sex differences in fear extinction.

Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval

Abstract Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate’s brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [ 11 C]raclopride’s binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [ 11 C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of “high”. We show for the first time that the “high” is associated with the fast dopamine increases induced by methylphenidate. 

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Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans

Sleep disturbances are very common in alcohol use disorder (AUD) and contribute to relapse. Detoxification appears to have limited effects on sleep problems. However, inter-individual differences and related brain mechanisms have not been closely examined. We examined N3 sleep and the associated brain functional and structural changes in 30 AUD patients (9 Females, mean age: 42 years) undergoing a 3-week inpatient detoxification. Patients’ N3 sleep, resting state functional connectivity (RSFC), grey matter volume (GMV) and negative mood were measured on week 1 and week 3. AUD patients did not show significant N3 sleep recovery after 3-weeks of detoxification. However, we observed large variability among AUD patients. Inter-individual variations in N3 increases were associated with increases in midline default mode network (DMN) RSFC but not with GMV using a whole-brain approach. Exploratory analyses revealed significant sex by detoxification effects on N3 sleep such that AUD females showed greater N3 increases than AUD males. Further, N3 increases fully mediated the effect of mood improvement on DMN RSFC increases. We show a significant relationship between N3 and DMN functional changes in AUD over time/abstinence. The current findings may have clinical implications for monitoring brain recovery in AUD using daily sleep measures, which might help guide individualized treatments. Future investigations on sex differences with a larger sample and with longitudinal data for a longer period of abstinence are needed. 

Dana E Feldman

Papers

Sex Differences in Context Fear Generalization and Recruitment of Hippocampus and Amygdala during Retrieval

Time-varying SUVr reflects the dynamics of dopamine increases during methylphenidate challenges in humans

Effect of detoxification on N3 sleep correlates with brain functional but not structural changes in alcohol use disorder.