A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior

Knoedler, Joseph R.; Inoue, Shuichiro; Bayless, Daniel W.; Yang, Taehong; Tantry, Adarsh; Davis, Chung-ha O.; Leung, Nicole Y.; Parthasarathy, S.; Wang, Grace; Alvarado, Maricruz; Rizvi, Abbas H.; Fenno, Lief E.; Ramakrishnan, Charu; Deisseroth, Karl; Shah, Nirao M.

doi:10.1016/j.cell.2021.12.031

Cited by 90 publications

(62 citation statements)

References 117 publications

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“…In line with our findings, human data indicates that male, but not female, Met66BDNF allele-carriers experience higher incidences of major depressive disorder [56]. In addition, sex differences in social behavior have been widely described [57][58][59][60][61][62], and are likely to be caused by differences in neuronal activity, receptor density and hormonal signaling. However, further studies are needed to determine whether BDNF in female mice plays a role in other behaviors, including gating alcohol use [63], which is mediated in part via corticostriatal circuitries [31].…”

Section: Discussionsupporting

confidence: 89%

“…Sex differences in social behavior have been widely described [54][55][56][57][58][59]. Interestingly, we observed sex differences in social behaviors between the male and female Met68BDNF mice.…”

Section: Discussionsupporting

confidence: 49%

“…In addition, sex differences in social behavior have been widely described [50][51][52][53][54][55]. However, further studies are needed to determine whether BDNF in female mice plays a role in other behaviors, including gating alcohol use, which is mediated in part via corticostriatal circuitries in male mice [14,[56][57][58].…”

Section: Discussionmentioning

confidence: 99%

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The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

Moffat

Sakhai

Hoisington

et al. 2022

Preprint

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The brain-derived neurotrophic factor (BDNF) Valine 66 to Methionine human polymorphism results in impaired activity-dependent BDNF release and has been linked to psychiatric disorders including anxiety and alcohol dependence. We previously showed that knock-in mice carrying the mouse Methionine homolog (Met68BDNF) exhibit excessive and compulsive alcohol drinking behaviors as compared to the wild-type Val68BDNF mice. Here, we set out to determine the potential mechanism for the heightened and compulsive alcohol drinking phenotype exhibited by the Met68BDNFmice. We found that male, but not female Met68BDNF mice show social anxiety-like behaviors. We further report that male, but not female, Met68BDNF mice are resistant to the anxiolytic effects and sedative actions of alcohol as compared to Val68BDNF mice. Alcohol-dependent hypolocomotion is also reduced in Met68BDNF. In contrast, alcohol place preference is similar in Met68BDNF compared with Val68BDNF mice. Finally, we show that the anxiolytic action of alcohol is restored in Met68BDNF mice by overexpressing the wild-type Val68BDNF in the ventral hippocampus (vHC). Together, our results suggest that heighted social anxiety and a lack of alcohol-dependent anxiolysis may contribute to excessive alcohol intake by constraining normal BDNF signaling in the vHC.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 49%

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The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

Moffat

Sakhai

Hoisington

et al. 2022

Preprint

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“…Of note, the protective effects of this brain profile were strongest among the fastest maturing adolescents (i.e., those showing higher pubertal hormone levels), in line with prior demonstrations of DA-mediated gonadal hormone effects on behaviour, including liability to MDD (63)(64)(65). More broadly, this profile speaks to the value of longitudinal investigations of DA-gonadal hormone (particularly estradiol) dynamics in uncovering fluctuating substrates of resilience as a function of adversity exposure and differential gene expression patterns, including those observed across the various menstrual cycle stages (63,66,67).…”

Section: Discussionmentioning

confidence: 99%

Psychological Resilience in Adolescence as a function of Genetic Risk for Major Depressive Disorder and Alzheimer’s Disease

Petrican

Fornito

2022

Preprint

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Major Depressive Disorder (MDD) and Alzheimer's Disease (AD) are two pathologies linked to prior stress exposure and altered neurodevelopmental trajectories. As a putative antecedent to AD, MDD could be key to understanding the neurobiological changes that precede the clinical onset of AD by decades. To test this hypothesis, we used longitudinal data from the Adolescent Brain and Cognitive Development study (Ntotal = 980, 470 females) and investigated overlapping connectomic, transcriptomic, and chemoarchitectural correlates of adjustment to stressors (i.e., resilience) among adolescents at genetic risk for AD and MDD, respectively. The potential for perinatal adversity to directly and/or indirectly, via accelerated biological ageing, foster resilience (i.e., "inoculation" effects) was also probed. We identified two distinguishable neurodevelopmental profiles predictive of resilience among MDD-vulnerable adolescents. One profile, expressed among the fastest developing youth, overlapped with areas of greater dopamine receptor density and reflected the maturational refinement of the inhibitory control architecture. The second profile distinguished resilient MDD-prone youth from psychologically vulnerable adolescents genetically predisposed towards AD. This profile, associated with elevated GABA, relative to glutamate, receptor density, captured the longitudinal refinement and increasing context specificity of incentive-related brain activations. Its transcriptomic signature implied that poorer resilience among AD-prone youth may be associated with greater expression of MDD-relevant genes. Our findings are compatible with the proposed role of MDD as a precursor to AD and underscore the pivotal contribution of incentive processing to this relationship. They further speak to the key neuromodulatory role of DA-gonadal hormone interactions in fostering resilience in adolescence.

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“…The activity of these neurons is necessary for lordosis, and their activity is modulated by hormonal state during the estrus cycle, positioning this population of cells as an important locus for integrating internal and-likely-sensory signals to control lordosis. RNA sequencing and chemogenic manipulations have further refined the identity of these cells, indicating that lordosis is specifically controlled by a cholecystokinin A receptor-expressing 10.3389/fncir.2022.944895 (Cckar+) subpopulation (Knoedler et al, 2022). In addition, a population of kisspeptin-expressing (kisspeptin+) neurons in the anteroventral periventricular area (AVPV) have been shown to be required for lordosis (Hellier et al, 2018).…”

Section: Ventromedial Hypothalamusmentioning

confidence: 99%

Cupid’s quiver: Integrating sensory cues in rodent mating systems

Hoglen

Manoli

2022

Front. Neural Circuits

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In many animal species, males and females exploit different mating strategies, display sex-typical behaviors, and use distinct systems to recognize ethologically relevant cues. Mate selection thus requires mutual recognition across diverse social interactions based on distinct sensory signals. These sex differences in courtship and mating behaviors correspond to differences in sensory systems and downstream neural substrates engaged to recognize and respond to courtship signals. In many rodents, males tend to rely heavily on volatile olfactory and pheromone cues, while females appear to be guided more by a combination of these chemosensory signals with acoustic cues in the form of ultrasonic vocalizations. The mechanisms by which chemical and acoustic cues are integrated to control behavior are understudied in mating but are known to be important in the control of maternal behaviors. Socially monogamous species constitute a behaviorally distinct group of rodents. In these species, anatomic differences between males and females outside the nervous system are less prominent than in species with non-monogamous mating systems, and both sexes engage in more symmetric social behaviors and form attachments. Nevertheless, despite the apparent similarities in behaviors displayed by monogamous males and females, the circuitry supporting social, mating, and attachment behaviors in these species is increasingly thought to differ between the sexes. Sex differences in sensory modalities most important for mate recognition in across species are of particular interest and present a wealth of questions yet to be answered. Here, we discuss how distinct sensory cues may be integrated to drive social and attachment behaviors in rodents, and the differing roles of specific sensory systems in eliciting displays of behavior by females or males.

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A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior

Cited by 90 publications

References 117 publications

The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

The BDNF Val68Met polymorphism causes a sex specific alcohol preference over social interaction and also acute tolerance to the anxiolytic effects of alcohol, a phenotype driven by malfunction of BDNF in the ventral hippocampus of male mice

Psychological Resilience in Adolescence as a function of Genetic Risk for Major Depressive Disorder and Alzheimer’s Disease

Cupid’s quiver: Integrating sensory cues in rodent mating systems

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