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Spicer, M. M.

Publications and source records attributed to Spicer, M. M..

3 recordsLinked to original sources

Timing, movement, and reward contributions to prefrontal and striatal ramping activity

Across species, prefrontal and striatal neurons exhibit time-dependent ramping activity, defined as a consistent monotonic change in firing rate across temporal intervals. However, it is unclear if ramping activity is related to the cognitive process of estimating time, or to other behavioral factors such as anticipating reward or regulating movements. Here, we harnessed two novel approaches to determine how these factors contribute to prefrontal and striatal ramping activity in mice performing an interval timing task. First, to determine how movement contributes to ramping activity, we tracked movement velocity using DeepLabCut as well as task-specific movements while recording prefrontal or striatal ensembles during interval timing. We found that time was more accurately decoded by ramping neurons than movement-modulated neurons, with the exception of prefrontal velocity-modulated neurons. Second, to disambiguate temporal signals from anticipatory reward signals we compared activity patterns in neurons that were recorded during interval timing to the same neurons recorded during a Pavlovian conditioning task. We found more ramping activity and more accurate temporal decoding by neuronal ensembles during interval timing compared to Pavlovian conditioning. Together, these data quantify contributions of time estimation, movement, and reward anticipation in prefrontal and striatal ensembles, and they suggest that ramping is a cognitive signal that estimates time. Our results provide insight into how prefrontal and striatal ensembles multiplex information to effect temporal control of action.

neuroscience↗

Regulator of G protein signaling 6 (RGS6) in ventral tegmental area (VTA) dopamine neurons promotes EtOH seeking, behavioral reward and susceptibility to relapse

Mesolimbic dopamine (DA) transmission is believed to play a critical role in mediating reward responses to drugs of abuse, including alcohol (EtOH). EtOH is the most abused substance worldwide with chronic consumption often leading to the development of dependence and abuse. Unfortunately, the neurobiological mechanisms underlying EtOH-seeking behavior and dependence are not fully understood, and abstinence remains the only effective way to prevent alcohol use disorders (AUDs). Here, we developed novel RGS6fl/fl; DAT-iCreER mice to determine the role of RGS6 in VTA DA neurons on EtOH consumption and reward behaviors. We found that RGS6 is expressed in DA neurons in both human and mouse VTA, and that RGS6 loss in mice upregulates DA transporter (DAT) expression in VTA DA neuron synaptic terminals. Remarkably, loss of RGS6 in VTA DA neurons significantly reduced EtOH consumption, preference, and reward in a manner indistinguishable from that seen in RGS6-/- mice. Strikingly, RGS6 loss from VTA DA neurons before or after EtOH behavioral reward is established significantly reduced ([~]50%) re-instatement of reward following extinguishment, demonstrating distinct roles of RGS6 in promoting reward and relapse susceptibility to EtOH. These studies illuminate a critical role of RGS6 in the mesolimbic circuit in promoting EtOH seeking, reward, and reinstatement. We propose that RGS6 functions to promote DA transmission through its function as a negative modulator of GPCR-Gi/o-DAT signaling in VTA DA neurons. These studies identify RGS6 as a potential therapeutic target for behavioral reward and relapse to EtOH.

neuroscience↗

RGS6 mediates exercise-induced recovery of hippocampal neurogenesis, learning, and memory in an Alzheimer's mouse model

Hippocampal neuronal loss causes cognitive dysfunction in Alzheimers disease (AD). Adult hippocampal neurogenesis (AHN) is reduced in AD patients. Exercise stimulates AHN in rodents and improves memory and slows cognitive decline in AD patients. However, the molecular pathways for exercise-induced AHN and improved cognition in AD are poorly understood. Here, we show that voluntary running in APPSWE mice restores their hippocampal cognitive impairments to that of control mice. This cognitive rescue was abolished by RGS6 deletion in dentate gyrus (DG) neuronal progenitors (NPs), which also abolished running-mediated increases in AHN. AHN was reduced in sedentary APPSWE mice versus control mice, with basal AHN reduced by RGS6 deletion in DG NPs. RGS6 expression is significantly lower in the DG of AD patients. Thus, RGS6 mediates exercise-induced rescue of impaired cognition and AHN in AD mice, identifying RGS6 in DG NPs as a potential target to combat hippocampal neuron loss in AD. TeaserRGS6 expression in hippocampal NPCs promotes voluntary running-induced neurogenesis and restored cognition in APPSWE mice. Field CodesRGS6, Alzheimers disease, adult hippocampal neurogenesis, neural precursor cells, dentate gyrus, exercise, learning/memory

neuroscience↗