Biology subjects

Tu, E. M.

Publications and source records attributed to Tu, E. M..

3 recordsLinked to original sources

bioRxiv2024

Gastrin Releasing Peptide Signaling in the Nucleus Accumbens Medial Shell Regulates Neuronal Excitability and Motivation

Neuropeptides are the largest class of neuromodulators. It has been shown that subpopulations of dopamine neurons express mRNA for the neuropeptide Gastrin-releasing peptide (GRP); however, its functional relevance in dopaminergic circuits is unknown. Here, we find that the GRP receptor (GRPR) is present in the nucleus accumbens medial shell (NAc MSh), which is targeted by GRP-expressing midbrain dopamine neurons as well as glutamatergic inputs from the hippocampus and amygdala. We show that the NAc MSh GRPR-positive cells are a subpopulation of D2 receptor-expressing neurons, comprising both classical indirect pathway striatal projection neurons (iSPNs) and eccentric SPNs (eSPNs), which have high intrinsic excitability, and can be activated by GRP in vivo. NAc-specific deletion of Grpr increases motivation in a progressive ratio test, demonstrating that GRPR regulates motivated behaviors. These experiments establish GRP/GRPR signaling as a potent modulator of mesolimbic circuits and advance our understanding of neuropeptide actions in the brain.

neuroscience↗

bioRxiv2024

Cntnap2 loss drives striatal neuron hyperexcitability and behavioral inflexibility

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by two major diagnostic criteria - persistent deficits in social communication and interaction, and the presence of restricted, repetitive patterns of behavior (RRBs). Evidence from both human and animal model studies of ASD suggest that alteration of striatal circuits, which mediate motor learning, action selection, and habit formation, may contribute to the manifestation of RRBs. CNTNAP2 is a syndromic ASD risk gene, and loss of function of Cntnap2 in mice is associated with RRBs. How loss of Cntnap2 impacts striatal neuron function is largely unknown. In this study, we utilized Cntnap2-/- mice to test whether altered striatal neuron activity contributes to aberrant motor behaviors relevant to ASD. We find that Cntnap2-/- mice exhibit increased cortical drive of direct pathway striatal projection neurons (dSPNs). This enhanced drive is likely due to increased intrinsic excitability of dSPNs, which make them more responsive to cortical inputs. We find that Cntnap2-/- mice exhibit spontaneous repetitive behaviors, increased motor routine learning, perseveration, and cognitive inflexibility. Increased corticostriatal drive of the direct pathway may therefore contribute to the acquisition of repetitive, inflexible behaviors in Cntnap2 mice.

neuroscience↗

bioRxiv2023

Nucleus accumbens dopamine release reflects Bayesian inference during instrumental learning

Dopamine release in the nucleus accumbens has been hypothesized to signal reward prediction error, the difference between observed and predicted reward, suggesting a biological implementation for reinforcement learning. Rigorous tests of this hypothesis require assumptions about how the brain maps sensory signals to reward predictions, yet this mapping is still poorly understood. In particular, the mapping is non-trivial when sensory signals provide ambiguous information about the hidden state of the environment. Previous work using classical conditioning tasks has suggested that reward predictions are generated conditional on probabilistic beliefs about the hidden state, such that dopamine implicitly reflects these beliefs. Here we test this hypothesis in the context of an instrumental task (a two-armed bandit), where the hidden state switches repeatedly. We measured choice behavior and recorded dLight signals reflecting dopamine release in the nucleus accumbens core. Model comparison among a wide set of cognitive models based on the behavioral data favored models that used Bayesian updating of probabilistic beliefs. These same models also quantitatively matched the dopamine measurements better than non-Bayesian alternatives. We conclude that probabilistic belief computation contributes to instrumental task performance in mice and is reflected in mesolimbic dopamine signaling.

animal behavior and cognition↗