Since the discovery of synaptic plasticity as the cellular correlate of learning and memory, strong overlaps between neural and cellular substrates of learning, drug addiction and stress-related disorders have been recognized. Yet it remains a major challenge to identify the neural circuits and synaptic mechanisms contributing to abnormalities in dopamine signaling induced by addictive drugs and adverse early life experiences. The major focus of the lab of Fereshteh S. Nugent, PhD, is the elucidation of synaptic and epigenetic mechanisms underlying reward learning, drug addiction and neuropsychiatric disorders such as depression, with particular emphasis on the midbrain dopamine system originating from the ventral tegmental area (VTA) and its control by the lateral habenula (LHb). Recent research seeks to gain a better understanding of the link between early childhood trauma and mental health disorders. It’s been shown that adverse early life experiences such as prolonged child neglect or abuse increase the risk of developing mental health disorders strongly linked to dopamine dysfunction, including drug addiction and psychiatric disorders.


We use a combined approach of in vitro electrophysiology, optogenetics, immunohistochemical, biochemical, epigenetic, and behavioral techniques to provide a mechanistic understanding of early life stress- and drug-induced neuroplasticity in brain reward circuits.


Our work has been funded by NIH/NIDA, NARSAD and DOD.

We demonstrated that early maternal deprivation in juvenile rats (an animal model of child abuse) selectively induces synaptic abnormalities within VTA dopamine neurons through epigenetic modifications of AKAP150, a scaffolding protein important for trafficking of synaptic receptors. Histone deacetylase (HDAC) inhibitors reversed these synaptic abnormalities and normalized AKAP signaling in maternally-deprived animals. These results suggest a mechanistic link between epigenetic modifications of synaptic regulation within the VTA and increased propensity to develop mental health disorders following maternal deprivation.

Read Publication

Also the related work in lateral habenula that was highlighted as the cover story of the magazine and also in the funding agency: Our most recent work (featured as the cover story of Science Signaling on March 6, 2018) provides evidence for the existence of corticotropin-releasing factor (CRF) signaling within the lateral habenula (LHb as a negative controller of dopamine neurons) and dysregulation of this extrahypothalamic CRF system within the LHb by early life stress. Our data suggest that recruitment of the CRF stress systems within the LHb may play a key role in the development of stress-, addiction- and depressive-related behaviors through changes in dopamine signaling. We have also found that ketamine exerts antidepressant effects on maternal deprivation-induced depressive-like behaviors and LHb hyperexcitability (that we found to persist up to adulthood in rats).

Read Publication

More About the Study >

Featured in Science Magazine >