Behavioral strategies are often classified based on whether reinforcer value controls reinforcement. Value-sensitive behaviors, in which animals update their actions when reinforcer value is changed, are classified as goal-directed; conversely, value-insensitive actions, where behavior remains consistent when the reinforcer is removed or devalued, are considered habitual. Basic reinforcement principles can help to bias behavior toward either process: random ratio (RR) schedules are thought to promote the formation of goal-directed behaviors while random intervals (RI) promote habitual control. However, how the schedule-specific features of these tasks interact with other factors that influence learning to control behavior has not been well characterized. Using male and female mice, we asked how distinct food restriction levels, a strategy often used to increase task engagement, interact with RR and RI schedules to control performance during task acquisition and devaluation procedures. We determined that fo...

The cerebellum communicates with brain areas critically involved in control of goal-directed behaviors including the prefrontal and orbitofrontal cortices and midbrain and basal ganglia structures. In particular, the posterior cerebellum is important for cognitive flexibility and has been implicated in alcohol and drug-related memory. We hypothesized that the cerebellum, through its multiple connections to reward-related brain circuitry, regulates alcohol consumption. To test this, we expressed inhibitory DREADDs (designer receptors exclusively activated by designer drugs) in molecular layer interneurons (MLIs) in anterior (IV-V) or posterior (VI-VIII) cerebellar lobules of male and female mice and activated them during alcohol drinking sessions. In a home-cage drinking paradigm, alcohol consumption was significantly decreased by clozapine-N-oxide (CNO) or deschloroclozapine (DCZ) administration in male mice expressing DREADDs in posterior but not anterior lobules. CNO/DCZ injections did not affect drinkin...

Drive from peripheral neurons is essential in almost all pain states, but pharmacological silencing of these neurons to effect analgesia has proved problematic. Reversible gene therapy using long-lived chemogenetic approaches is an appealing option. We used the genetically-activated chloride channel PSAM4-GlyR to examine pain pathways in mice. Using recombinant AAV9-based delivery to sensory neurons, we found a reversal of acute pain behavior and diminished neuronal activity using in vitro and in vivo GCaMP imaging upon activation of PSAM4-GlyR with varenicline. A significant reduction in inflammatory heat hyperalgesia and oxaliplatin-induced cold allodynia was also observed. Importantly, there was no impairment of motor coordination, but innocuous von Frey sensation was inhibited. We generated a transgenic mouse that expresses a CAG-driven FLExed PSAM4-GlyR downstream of the Rosa26 locus that requires Cre recombinase to enable the expression of PSAM4-GlyR and tdTomato. We used NaV1.8 Cre to examine the ro...

Recent work in Drosophila has uncovered several neighboring classes of sleep-regulatory neurons within the central complex. However, the logic of connectivity and network motifs remains limited by the incomplete examination of relevant cell types. Using a recent genetic-anatomical classification of ellipsoid body ring neurons, we conducted a thermogenetic screen in female flies to assess sleep/wake behavior and identified two wake-promoting drivers that label ER3d neurons and two sleep-promoting drivers that express in ER3m cells. We then used intersectional genetics to refine driver expression patterns. Activation of ER3d cells shortened sleep bouts, suggesting a key role in sleep maintenance. While sleep-promoting drivers from our miniscreen label overlapping ER3m neurons, intersectional strategies cannot rule out sleep regulatory roles for additional neurons in their expression patterns. Suppressing GABA synthesis in ER3m neurons prevents post-injury sleep, and GABAergic ER3d cells are required for ther...

Obesity affects more than a third adult population in the United States; the prevalence is even higher in patients with major depression disorders. GWAS studies identify the receptor tyrosine kinase ErbB4 as a risk gene for obesity and for major depression disorders. We found that ErbB4 was enriched in the paraventricular nucleus of the hypothalamus (PVH). To investigate its role in metabolism, we deleted ErbB4 by injecting a Cre-expressing virus into the PVH of ErbB4 floxed male mice and found that PVH ErbB4 deletion increased weight gain without altering food intake. ErbB4 PVH deletion also reduced nighttime activity and decreased intrascapular brown adipose tissue (iBAT) thermogenesis. Analysis of covariance revealed that ErbB4 PVH deletion reduced O2 consumption, CO2 production and heat generation in a manner independent of body weight. Immunostaining experiments show that ErbB4+ neurons in the PVH were positive for oxytocin (OXT); ErbB4 PVH deletion reduces serum levels of OXT. To test this hypothesis...

Rapid saccadic eye movements are used by animals to sample different parts of the visual scene. Previous work has investigated neural correlates of these saccades in visual cortical areas such as V1; however, how saccade-responsive neurons are distributed across visual areas, cell types, and cortical layers has remained unknown. Through analyzing 818 1 h experimental sessions from the Allen Brain Observatory, we present a large-scale analysis of saccadic behaviors in head-fixed mice and their neural correlates. We find that saccade-responsive neurons are present across visual cortex, but their distribution varies considerably by transgenically defined cell type, cortical area, and cortical layer. We also find that saccade-responsive neurons do not exhibit distinct visual response properties from the broader neural population, suggesting that the saccadic responses of these neurons are likely not predominantly visually driven. These results provide insight into the roles played by different cell types withi...

Neuropathic pain is stubborn and associated with the peripheral nerve regeneration process. Nicotine has been found to reduce pain, but whether it is involved in the regulation of nerve regeneration and the underlying mechanism are unknown. In this study, we examined the mechanical allodynia thermal hyperalgesia together with the peripheral nerve regeneration after nicotine exposure in two rat neuropathic pain models. In the spinal nerve ligation model, in which anatomic nerve regeneration can be easily observed, nicotine reduced anatomic measures of regeneration as well as expression of regeneration marker growth-associated protein 43 (GAP43). In the tibial nerve crush model, nicotine treatment significantly suppressed GAP43 expression and functional reinnervation as measured by myelinated action potential and electromyography of gastrocnemius. In both models, nicotine treatment reduced macrophage density in the sensory ganglia and peripheral nerve. These effects of nicotine were reversed by the selective...

To survive, animals must meet their biological needs while simultaneously avoiding danger. However, the neurobiological basis of appetitive and aversive survival behaviors has historically been studied using separate behavioral tasks. While recent studies in mice have quantified appetitive and aversive conditioned responses simultaneously ([Jikomes et al., 2016][1]; [Heinz et al., 2017][2]), these tasks required different behavioral responses to each stimulus. As many brain regions involved in survival behavior process stimuli of opposite valence, we developed a paradigm in which mice perform the same response (nose poke) to distinct auditory cues to obtain a rewarding outcome (palatable food) or avoid an aversive outcome (mild footshoock). This design allows for both within-subject and between-subject comparisons as animals respond to appetitive and aversive cues. The central nucleus of the amygdala (CeA) is implicated in the regulation of responses to stimuli of either valence. Considering its role in th...

Recent work in Drosophila has uncovered several neighboring classes of sleep-regulatory neurons within the central complex. However, the logic of connectivity and network motifs remains limited by the incomplete examination of relevant cell types. Using a recent genetic–anatomic classification of ellipsoid body ring neurons, we conducted a thermogenetic screen in female flies to assess sleep/wake behavior and identified two wake-promoting drivers that label ER3d neurons and two sleep-promoting drivers that express in ER3m cells. We then used intersectional genetics to refine driver expression patterns. Activation of ER3d cells shortened sleep bouts, suggesting a key role in sleep maintenance. While sleep-promoting drivers from our mini-screen label overlapping ER3m neurons, intersectional strategies cannot rule out sleep regulatory roles for additional neurons in their expression patterns. Suppressing GABA synthesis in ER3m neurons prevents postinjury sleep, and GABAergic ER3d cells are required for thermo...

Stress alters social functioning in a complex manner. An important variable determining the final effects of stress is stressor intensity. However, the precise relationship between stressor intensity and social behavior is not well understood. Here, we investigate the effects of varying acute stressor intensity exposure on social behavior using adult zebrafish. We first establish a novel test using adult zebrafish that allows distinguishing fish’s drive to approach a social cue and its ability to engage and maintain social interaction within the same behavioral paradigm. Next, we combined this test with a new method to deliver an acute stress stimulus of varying intensities. Our results show that both social approach and social maintenance are reduced in adult zebrafish on acute stress exposure in an intensity-dependent manner. Interestingly, lower stress intensity reduces social maintenance without affecting the social approach, while a higher stress level is required to alter social approach. These resul...