Cilia loss on distinct neuron populations differentially alters cocaine-induced locomotion and reward.

BACKGROUND: Neuronal primary cilia are being recognized for their role in mediating signaling associated with a variety of neurobehaviors, including responses to drugs of abuse. They function as signaling hubs, enriched with a diverse array of G-protein coupled receptors (GPCRs), including several associated with motivation and drug-related behaviors. However, our understanding of how cilia regulate neuronal function and behavior is still limited. AIMS: The objective of the current study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to cocaine. METHODS: To test the consequences of cilia loss on cocaine-induced locomotion and reward-related behavior, we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. RESULTS: Cilia ablation on either population of neurons failed to significantly alter acute locomotor responses to cocaine at a range of doses. With repeated administration, mice lacking cilia on GAD2-GABAergic neurons showed no difference in locomotor sensitization to cocaine compared to wild-type (WT) littermates, whereas mice lacking cilia on dopaminergic neurons exhibited reduced locomotor sensitization to cocaine at 10 and 30 mg/kg. Mice lacking cilia on GAD2-GABAergic neurons showed no difference in cocaine conditioned place preference (CPP), whereas mice lacking cilia on dopaminergic neurons exhibited reduced CPP compared to WT littermates. CONCLUSIONS: Combined with previous findings using amphetamine, our results show that behavioral effects of cilia ablation are cell- and drug type-specific, and that neuronal cilia contribute to modulation of both the locomotor-inducing and rewarding properties of cocaine.

GABAB receptors in prelimbic cortex and basolateral amygdala differentially influence intertemporal decision making and decline with age.

The ability to decide adaptively between immediate vs. delayed gratification (intertemporal choice) is critical for well-being and is associated with a range of factors that influence quality of life. In contrast to young adults, many older adults show enhanced preference for delayed gratification; however, the neural mechanisms underlying this age difference in intertemporal choice are largely un-studied. Changes in signaling through GABAB receptors (GABABRs) mediate several age-associated differences in cognitive processes linked to intertemporal choice. The current study used a rat model to determine how GABABRs in two brain regions known to regulate intertemporal choice (prelimbic cortex; PrL and basolateral amygdala; BLA) contribute to age differences in this form of decision making in male rats. As in humans, aged rats showed enhanced preference for large, delayed over small, immediate rewards during performance in an intertemporal choice task in operant test chambers. Activation of PrL GABABRs via microinfusion of the agonist baclofen increased choice of large, delayed rewards in young adult rats but did not influence choice in aged rats. Conversely, infusion of baclofen into the BLA strongly reduced choice of large, delayed rewards in both young adult and aged rats. Aged rats further showed a significant reduction in expression of GABABR1 subunit isoforms in the prefrontal cortex, a discovery that is consonant with the null effect of intra-PrL baclofen on intertemporal choice in aged rats. In contrast, expression of GABABR subunits was generally conserved with age in the BLA. Jointly, these findings elucidate a role for GABABRs in intertemporal choice and identify fundamental features of brain maturation and aging that mediate an improved ability to delay gratification.

Regulation of risky decision making by gonadal hormones in males and females.

Psychiatric diseases characterized by dysregulated risky decision making are differentially represented in males and females. The factors that govern such sex differences, however, remain poorly understood. Using a task in which rats make discrete trial choices between a small, "safe" food reward and a large food reward accompanied by varying probabilities of footshock punishment, we recently showed that females are more risk averse than males. The objective of the current experiments was to test the extent to which these sex differences in risky decision making are mediated by gonadal hormones. Male and female rats were trained in the risky decision-making task, followed by ovariectomy (OVX), orchiectomy (ORX), or sham surgery. Rats were then retested in the task, under both baseline conditions and following administration of estradiol and/or testosterone. OVX increased choice of the large, risky reward (increased risky choice), an effect that was attenuated by estradiol administration. In contrast, ORX decreased risky choice, but testosterone administration was without effect in either ORX or sham males. Estradiol, however, decreased risky choice in both groups of males. Importantly, none of the effects of hormonal manipulation on risky choice were due to altered shock sensitivity or food motivation. These data show that gonadal hormones are required for maintaining sex-typical profiles of risk-taking behavior in both males and females, and that estradiol is sufficient to promote risk aversion in both sexes. The findings provide novel information about the mechanisms supporting sex differences in risk taking and may prove useful in understanding sex differences in the prevalence of psychiatric diseases associated with altered risk taking.

Neuron-specific cilia loss differentially alters locomotor responses to amphetamine in mice.

The neural mechanisms that underlie responses to drugs of abuse are complex, and impacted by a number of neuromodulatory peptides. Within the past 10 years it has been discovered that several of the receptors for neuromodulators are enriched in the primary cilia of neurons. Primary cilia are microtubule-based organelles that project from the surface of nearly all mammalian cells, including neurons. Despite what we know about cilia, our understanding of how cilia regulate neuronal function and behavior is still limited. The primary objective of this study was to investigate the contributions of primary cilia on specific neuronal populations to behavioral responses to amphetamine. To test the consequences of cilia loss on amphetamine-induced locomotor activity we selectively ablated cilia from dopaminergic or GAD2-GABAergic neurons in mice. Cilia loss had no effect on baseline locomotion in either mouse strain. In mice lacking cilia on dopaminergic neurons, locomotor activity compared to wild- type mice was reduced in both sexes in response to acute administration of 3.0 mg/kg amphetamine. In contrast, changes in the locomotor response to amphetamine in mice lacking cilia on GAD2-GABAergic neurons were primarily driven by reductions in locomotor activity in males. Following repeated amphetamine administration (1.0 mg kg-1  day-1 over 5 days), mice lacking cilia on GAD2-GABAergic neurons exhibited enhanced sensitization of the locomotor stimulant response to the drug, whereas mice lacking cilia on dopaminergic neurons did not differ from wild-type controls. These results indicate that cilia play neuron-specific roles in both acute and neuroplastic responses to psychostimulant drugs of abuse.

Testicular hormones mediate robust sex differences in impulsive choice in rats.

Impairments in choosing optimally between immediate and delayed rewards are associated with numerous psychiatric disorders. Such 'intertemporal' choice is influenced by genetic and experiential factors; however, the contributions of biological sex are understudied and data to date are largely inconclusive. Rats were used to determine how sex and gonadal hormones influence choices between small, immediate and large, delayed rewards. Females showed markedly greater preference than males for small, immediate over large, delayed rewards (greater impulsive choice). This difference was neither due to differences in food motivation or reward magnitude perception, nor was it affected by estrous cycle. Ovariectomies did not affect choice in females, whereas orchiectomies increased impulsive choice in males. These data show that male rats exhibit less impulsive choice than females and that this difference is at least partly maintained by testicular hormones. These differences in impulsive choice could be linked to gender differences across multiple neuropsychiatric conditions.

Optogenetic dissection of basolateral amygdala contributions to intertemporal choice in young and aged rats.

Across species, aging is associated with an increased ability to choose delayed over immediate gratification. These experiments used young and aged rats to test the role of the basolateral amygdala (BLA) in intertemporal decision making. An optogenetic approach was used to inactivate the BLA in young and aged rats at discrete time points during choices between levers that yielded a small, immediate vs. a large, delayed food reward. BLA inactivation just prior to decisions attenuated impulsive choice in both young and aged rats. In contrast, inactivation during receipt of the small, immediate reward increased impulsive choice in young rats but had no effect in aged rats. BLA inactivation during the delay or intertrial interval had no effect at either age. These data demonstrate that the BLA plays multiple, temporally distinct roles during intertemporal choice, and show that the contribution of BLA to choice behavior changes across the lifespan.