Anirudh Gaur

Research Description

Cognitive flexibility is a critical executive function, deficits in which are found in multiple neurological and psychological disorders including OCD, bipolar and mood disorders, Parkinson’s disease, Alzheimer’s and substance use disorder [3] and declines precipitously with age even in humans with no neurological disease. One of the key challenges in treatment of these diverse neurological disorders is that the existing pharmacological agents, including antidepressants and anti-psychotics are not effective at treating the cognitive deficits and have serious side effects including exacerbation of cognitive deficit, insomnia, nausea, fatigue and risk of addiction. Hence there is a need to develop better and safer treatments to replace or supplement existing drugs if we want to stabilize the cognitive impairments associated with disease or age.

Several recent studies have described the neuroprotective effects of the neuroendocrine incretin hormone – Glucagon-Like Peptide 1 (GLP-1) on brain structure and function. GLP-1 and its cognate GLP-1 receptor (GLP1R) are present in key regions of the brain implicated in memory and decision making, including both the hippocampus and ventral tegmental area (VTA), whose dopamine (DA) neurons are thought to play a critical role in regulating entry of information into long-term memory via hippocampal-VTA loop. Furthermore, there is significant evidence that incretin signaling in these brain regions modulates learning and memory. In preclinical animal models, these drugs have been shown to protect long-term potentiation (LTP) and to produce improved performance in several diverse cognitive tasks. We were intrigued by the observation that activation of the GLP1R with incretin drug in the VTA modifies not only food intake but also reward seeking behavior, and hypothesized, that GLP1Rs in the VTA could modulate dopamine dynamics to gate memory and learning. Indeed, I have recently found, using the dLight DA sensor and fiber photometry, that systemic administration of the incretin drug liraglutide alters dopamine dynamics in the medial nucleus accumbens (NAc) in mice and can block changes in dopamine release in the NAc produced by the rewarding drug morphine. Cumulatively, our data and that previously reported have led us to hypothesize that incretin drugs could be used to improve cognitive deficits.