ventral tegmental area

Molecular strategies for resolving differential regulation of dopamine subpopulations

Project Summary/Abstract Dopamine neurons in the ventral tegmental area (VTA) fire action potentials in complex patterns of tonic and phasic activity in response to environmental stimuli and during behavioral tasks. Transcriptomic, anatomical, and functional studies have established that VTA dopamine neurons can be divided into multiple subpopulations with variable gene expression, projection patterns, and response profiles. We recently completed a transcriptomic study that identified genetic markers for three distinct subpopulations of VTA dopamine neurons, and also found evidence for variability in ion channel gene expression between populations that correlated with differences in activity-dependent gene expression. However, much remains unknown regarding how specific genes encoding ion channels, receptors, transcription factors, or other signaling components contribute to the variability in baseline physiological properties observed across the VTA. Here we propose to combine slice electrophysiology recordings of VTA dopamine neurons with post-hoc single-cell sequencing analysis (i.e. patch-seq), which will allow us to directly correlate gene expression and physiological properties in order to identify candidate genes that may be key drivers of the variability between subpopulations. We also propose to validate and utilize a novel dual-recombinase CRISPR/Cas9 system for targeted gene mutagenesis in intersectional neuronal populations, which will provide a mechanism for testing gene function with unprecedented precision. We will use this approach to test the function of two candidate ion channel genes, the potassium channels Kcnh5 and Kcnh7, previously identified in our transcriptomic study as potential contributors to dopamine neuron action potential firing properties. We hypothesize that these genes are important for enabling rapid action potential firing in highly excitable dopamine neurons found in specific subpopulations. As a whole, with this proposal we aim to generate a valuable dataset linking gene expression in VTA dopamine neurons with physiology and subpopulation identification, as well as develop an intersectional gene mutagenesis strategy that can be used throughout the brain to precisely target neuronal subpopulations to test gene function. With this approach, we hope to facilitate future precision targeting of the dopamine system and dopamine-dependent behaviors.

How do we sleep?

There is no consensus on if sleep is for the brain, body or both. But the difference in how we feel following disrupted sleep or having a good night of continuous sleep is striking. Understanding how and why we sleep will likely give insights into many aspects of health. In this talk I will outline our recent work on how the prefrontal cortex can signal to the hypothalamus to regulate sleep preparatory behaviours and sleep itself, and how other brain regions, including the ventral tegmental area, respond to psychosocial stress to induce beneficial sleep. I will also outline our work on examining the function of the glymphatic system, and whether clearance of molecules from the brain is enhanced during sleep or wakefulness.

Learning to Express Reward Prediction Error-like Dopaminergic Activity Requires Plastic Representations of Time

The dominant theoretical framework to account for reinforcement learning in the brain is temporal difference (TD) reinforcement learning. The TD framework predicts that some neuronal elements should represent the reward prediction error (RPE), which means they signal the difference between the expected future rewards and the actual rewards. The prominence of the TD theory arises from the observation that firing properties of dopaminergic neurons in the ventral tegmental area appear similar to those of RPE model-neurons in TD learning. Previous implementations of TD learning assume a fixed temporal basis for each stimulus that might eventually predict a reward. Here we show that such a fixed temporal basis is implausible and that certain predictions of TD learning are inconsistent with experiments. We propose instead an alternative theoretical framework, coined FLEX (Flexibly Learned Errors in Expected Reward). In FLEX, feature specific representations of time are learned, allowing for neural representations of stimuli to adjust their timing and relation to rewards in an online manner. In FLEX dopamine acts as an instructive signal which helps build temporal models of the environment. FLEX is a general theoretical framework that has many possible biophysical implementations. In order to show that FLEX is a feasible approach, we present a specific biophysically plausible model which implements the principles of FLEX. We show that this implementation can account for various reinforcement learning paradigms, and that its results and predictions are consistent with a preponderance of both existing and reanalyzed experimental data.

Brain coding of maternal behaviour: role of the tail of the ventral tegmental area

Central amygdala - ventral tegmental area – cortical circuits mediate initiation and maintenance of social interaction

Communication Between the Hippocampus, Nucleus Accumbens and Ventral Tegmental Area During Learning and Memroy

Deep brain stimulation of the ventral tegmental area to control positive symptoms of schizophrenia: a case report

Dopamine correlates of habit versus goal-directed behavior in the ventral tegmental area

Maternal immune activation decreases the E/I balance and activity of dopaminergic neurons in the ventral tegmental area

Responses to acoustic stimuli in the ventral tegmental area of freely-moving mice

RXFP3 expression in dopaminergic neurons of the hypothalamus and the ventral tegmental area of mice

Somatostatin-expressing neurons from the ventral tegmental area innervate distant brain regions

Ventral Tegmental Area glutamatergic neurons play a role in fear-induced hypophagia through lateral hypothalamic glutamatergic inputs

Activation of group II metabotropic glutamate receptors rescues the ventral hippocampus-ventral tegmental area circuit from amphetamine sensitization

FENS Forum 2024

Anatomofunctional characterization of the tail of the ventral tegmental area (tVTA/RMTg) in mice

FENS Forum 2024

Communication between the hippocampus, nucleus accumbens, and ventral tegmental area during learning and memory

FENS Forum 2024

Comparative examination of the ventral tegmental area in wild type and pituitary adenylate cyclase-activating polypeptide (PACAP) knockout mice

FENS Forum 2024

Diverse representation of various rewards in the dopaminergic neurons of the ventral tegmental area

FENS Forum 2024

The mu-opioid receptors in the ventral tegmental area contribute to the high heroin preference shown by Marchigian Sardinian alcohol-preferring rats

FENS Forum 2024

Nicotine exposure during adolescence disrupts the dopaminergic circuitry in the ventral tegmental area

FENS Forum 2024

The parabrachial nucleus recruits ventral tegmental area to convey negative emotions and disengage instrumental food seeking

FENS Forum 2024

Psychosocial and physical stress modulate noradrenergic signaling in the ventral tegmental area-nucleus accumbens circuit

FENS Forum 2024

Reduced local GABA transmission onto ventral tegmental area dopamine neurons underlies vulnerability for hyperactivity in a mouse model of anorexia nervosa

FENS Forum 2024

The role of the mu opioid receptors in the ventral tegmental area in the modulation of phasic dopamine release

FENS Forum 2024

Roles of the central amygdala to ventral tegmental area projections in fear regulation and the mechanism study

FENS Forum 2024