Department of Pharmacology

Department of
Psychiatry & Behavioral Sciences

 

The Zweifel Lab

Background and Summary of Previous Findings

Dopamine release into target brain regions can either be tonic (low steady levels of neurotransmitter) or phasic (transient high concentrations of neurotransmitter). These patterns are thought to play distinct roles in modulating the function of numerous circuits in the brain that regulate motor function, motivation, and emotion. The mechanisms responsible for determining these patterns of activity are thought to involve distinct neurotransmitter systems impinging upon dopamine neurons, as well as a complement of neurotransmitter receptors and ion channels. We discovered that the NMDA-type glutamate receptor works in a cell-autonomous manner to regulate phasic activation of dopamine neurons and that genetic inactivation of the gene encoding the essential subunit of the NMDA receptor (Grin1) impairs an animal’s ability to learn outcome contingencies effectively. We also have discovered that a mutation in the calcium activated potassium channel SK3 identified in a patient with schizophrenia potently enhances phasic activation of dopamine neurons. Selective expression of this mutation in dopamine neurons perturbs behavior leading to many phenotypes associated with mental illness. Utilizing genetic techniques we are now beginning to unravel how these genes influence circuit dynamics in the brain that are responsible for regulating numerous behaviors.

Current Projects

Phasic dopamine and fear.
We previously demonstrated that inactivation of NMDA receptors in dopamine neurons impairs an animal’s ability to ascribe fear to a specific stimulus, resulting in fear generalization (Zweifel et al., 2011). Moving this forward we demonstrated that a subset of dopamine neurons in the VTA undergo plasticity following fear conditioning using in vivo calcium imaging of genetically identified dopamine neurons (Gore et al., 2014). Utilizing in vivo electrophysiological recordings from the lateral amygdala in animals lacking NMDA receptors in dopamine neurons we have discovered that fear generalization is associated with failed plasticity in neurons of this brain region that impairs effective discrimination coding (Jones et al., submitted). Moving forward we are determining how phasic dopamine influences the physiology of neurons in this area of the brain and the link between plasticity in dopamine neurons and plasticity in the amygdala.

Corticotrophin Releasing Factor and Fear.
CRF is a key stress associated neuropeptide implicated in the regulation of anxiety and fear behavior. We have recently found through in vivo imaging, electrophysiology, and behavior that CRF-producing in the central nucleus of amygdala respond to fear-predictive cues, undergo plasticity following fear conditioning, and facilitate cued fear discrimination. We have also found that CRF itself produced in the CeA facilitates cued fear discrimination, but only at fear intensities below the threshold of fear generalization (Sanford et al., In revision). Moving forward we a mapping the specific connections of CRF neurons that mediate these functions.

Phasic dopamine and cortico-striatal connectivity.
We recently discovered that expression of the human SK3 delta mutation in dopamine neurons disrupts activity pattern regulation by these cells resulting in the manifestation of behaviors relevant to mental illness (Soden et al., 2011). We are now working to decipher how altering the activity patterns of dopamine neurons through this mutation impacts cortico-striatal networks. To achieve this we are performing combinatorial viral vector based approaches to selectively manipulate gene expression in dopamine neurons that make specific synaptic connections and performing in vivo calcium imaging of network dynamics in the ventral striatum.

Sexual dimorphism of dopamine systems.
There are numerous dopamine systems in the brain. The most commonly studied dopamine circuits are the nigrostriatal and mesolimbic dopamine circuits. Previous studies have described sex-specific differences in these ciruits, but a comprehensive examination of these differences is lacking. To address this we are performing translational profiling of dopamine neurons in these areas in male and female animals, mapping cell-specific circuit connectivity, and characterizing cell specific electrophysiological properties. In addition to the canonical dopamine pathways, we are study other dopaminergic nuclei and circuits that regulate numerous behaviors relevant to mental illness.

Dopamine and the cerebellum.
The dentate (or lateral) nucleus of the cerebellum (DNC) is a deep cerebellar structure that segregates into anatomically distinct regions thought to confer differential regulation of motor and non-motor operations. Dopamine is well known to exist in the cerebellum, but how it influences the DNC and non-motor function has not been resolved. Utilizing viral and genetic strategies in we have identified a novel population of dopamine D1 receptor-expressing neurons within the DNC that are anatomically segregated and have molecular, electrophysiological, and anatomical profiles of glycinergic and GABAergic neurons. Selective silencing of these neurons disrupts specific non-motor behaviors, including spatial memory, social preference, and anxiety. We are now characterizing the impact of dopamine on these neurons as well as identifying other novel dopaminergic circuits within the cerebellum.

Funding:

We are tremendously thankful for the generous financial support of our research by the US National Institutes of Health and the University of Washington.

Ongoing Research Support

R01MH094536, NIMH, 9/2011-8/2016, Zweifel (PI)
R01MH104450, NIMH, 3/2015-3/2020, Zweifel (PI)
P50MH106428, NIMH, 4/2015-3/2020, Zweifel (PI), Charles Chavkin (Administrative PI)
UW Innovator, University of Washington, 1/2015-1/2017, Zweifel (PI)

Recently Completed Research Support

R21MH098177, NIMH, 8/2012-7/2014, Zweifel (PI)