Cell-Specific Targeting of Genetically Encoded Tools for Neuroscience.

Genetically encoded tools for visualizing and manipulating neurons in vivo have led to significant advances in neuroscience, in large part because of the ability to target expression to specific cell populations of interest. Current methods enable targeting based on marker gene expression, development, anatomical projection pattern, synaptic connectivity, and recent activity as well as combinations of these factors. Here, we review these methods, focusing on issues of practical implementation as well as areas for future improvement.

Lessons from the Stories of Women in Neuroscience.

Women have been contributing to the field of neuroscience since its inception, but their accomplishments are often overlooked. Lack of recognition, among other issues, has led to progressively fewer women at each academic stage; although half of neuroscience graduate students are women, women comprise less than one-third of neuroscience faculty, and even fewer full professors. Those who reach this level continue to struggle to get their work recognized. Women from historically excluded backgrounds are even more starkly underrepresented and face added challenges related to racial, ethnic, and other biases. To increase the visibility of women in neuroscience, promote their voices, and learn about their career journeys, we created Stories of Women in Neuroscience (Stories of WiN). Stories of WiN shares the scientific and personal stories of women neuroscientists with diverse backgrounds, identities, research interests, and at various career stages. From >70 women highlighted thus far, a major theme has emerged: there is not a single archetype of a woman neuroscientist, nor a single path to "success." Yet, through these diverse experiences run common threads, such as the importance of positive early research experiences, managing imposter syndrome, the necessity of work-life balance, and the challenges of fitting into-or resisting-the "scientist mold" within a patriarchal, racialized academic system. These commonalities reveal important considerations for supporting women neuroscientists. Through the lens of women highlighted by Stories of WiN, we explore the similarities among their journeys and detail specific actionable items to help encourage, support, and sustain women in neuroscience.

Activity-based anorexia during adolescence disrupts normal development of the CA1 pyramidal cells in the ventral hippocampus of female rats.

Anorexia nervosa (AN) is a psychiatric illness characterized by restricted eating and irrational fears of gaining weight. There is no accepted pharmacological treatment for AN, and AN has the highest mortality rate among psychiatric illnesses. Anorexia nervosa most commonly affects females during adolescence, suggesting an effect of sex and hormones on vulnerability to the disease. Activity-based anorexia (ABA) is a rodent model of AN that shares symptoms with AN, including over-exercise, elevation of stress hormones, and genetic links to anxiety traits. We previously reported that ABA in adolescent female rats results in increased apical dendritic branching in CA1 pyramidal cells of the ventral hippocampus at postnatal day 44 (P44). To examine the long-term effects of adolescent ABA (P44) in female rats, we compared the apical branching in the ventral hippocampal CA1 after recovery from ABA (P51) and after a relapse of ABA (P55) with age-matched controls. To examine the age-dependence of the hippocampal plasticity, we examined the effect of ABA during adulthood (P67). We found that while ABA at P44 resulted in increased branching of ventral hippocampal pyramidal cells, relapse of ABA at P55 resulted in decreased branching. ABA induced during adulthood did not have an effect on dendritic branching, suggesting an age-dependence of the vulnerability to structural plasticity. Cells from control animals were found to exhibit a dramatic increase in branching, more than doubling from P44 to P51, followed by pruning from P51 to P55. The proportion of mature spines on dendrites from the P44-ABA animals is similar to that on dendrites from P55-CON animals. These results suggest that the experience of ABA may cause precocious anatomical development of the ventral hippocampus. Importantly, we found that adolescence is a period of continued development of the hippocampus, and increased vulnerability to mental disorders during adolescence may be due to insults during this developmentally critical period.

Cocaine Place Conditioning Strengthens Location-Specific Hippocampal Coupling to the Nucleus Accumbens.

Conditioned place preference (CPP) is a widely used model of addiction-related behavior whose underlying mechanisms are not understood. In this study, we used dual site silicon probe recordings in freely moving mice to examine interactions between the hippocampus and nucleus accumbens in cocaine CPP. We found that CPP was associated with recruitment of D2-positive nucleus accumbens medium spiny neurons to fire in the cocaine-paired location, and this recruitment was driven predominantly by selective strengthening of coupling with hippocampal place cells that encode the cocaine-paired location. These findings provide in vivo evidence suggesting that the synaptic potentiation in the accumbens caused by repeated cocaine administration preferentially affects inputs that were active at the time of drug exposure. This provides a potential physiological mechanism by which drug use becomes associated with specific environmental contexts.

Reverse pharmacogenetic modulation of the nucleus accumbens reduces ethanol consumption in a limited access paradigm.

Bilateral stereotactic lesioning of the nucleus accumbens (NAc) core reduces relapse rates in alcohol-dependent patients but may cause irreversible cognitive deficits. Deep brain stimulation has similar effects but requires costly implanted hardware and regular surgical maintenance. Therefore, there is considerable interest in refining these approaches to develop reversible, minimally invasive treatments for alcohol dependence. Toward this end, we evaluated the feasibility of a reverse pharmacogenetic approach in a preclinical mouse model. We first assessed the predictive validity of a limited access ethanol consumption paradigm by confirming that electrolytic lesions of the NAc core decreased ethanol consumption, recapitulating the effects of similar lesions in humans. We then used this paradigm to test the effect of modulating activity in the NAc using the Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) hM3Dq and hM4Di. We found that increasing activity with hM3Dq had no effect, but suppressing activity with hM4Di reduced alcohol consumption to a similar extent as lesioning without affecting consumption of water or sucrose. These results may represent early steps toward a novel neurosurgical treatment modality for alcohol dependence that is reversible and externally titratable, yet highly targetable and less invasive than current approaches such as lesioning or deep brain stimulation.