Overview

Research in the IGS lab revolves around two inter-related main subjects: (1) The molecular substrates of cognitive dysfunction, and (2) epigenetic mechanisms underlying the impact of stress on behavior. We use diverse genetic, molecular and behavior tools in mouse and rat models to address our research questions.

(1) The molecular substrates of cognitive dysfunction

Our cognitive capacities are defined by our ability to acquire new information, retain it and use it according to changing environmental demands. Cognitive dysfunction (i.e., deficits in memory, learning and attention) characterizes many psychiatric and neurological disorders. In schizophrenia, for example, cognitive dysfunction is argued to ‘set the stage’ for the eruption of full-blown psychosis. However, in schizophrenia as well as other disorders, cognitive symptoms remain mostly treatment-resistant.

Glutamate transmission in the prefrontal cortex (PFC) and hippocampal formation is critical for intact cognitive function. Disrupted glutamate transmission in rats and mice leads to cognitive deficits, but the precise nature of this disruption and its relevance to psychopathology remains to be determined. For example, in schizophrenia it is unclear whether glutamate abnormalities are the primary driver of disease or are secondary to abnormalities in other neurotransmitter systems (e.g., GABA or dopamine).

In our lab, we use genetic and pharmacological manipulations in mice and rats as tools to assess the relevance of glutamate transmission to cognitive dysfunction. We have developed a battery of behavioral assays capable of detecting abnormalities relevant to different aspects of cognition, e.g., aberrant salience, novelty recognition and attentional flexibility. This combination of tests allows us to examine individual variability and construct a scale of vulnerability or susceptibility to genetic or environmental manipulations. We use genetic and molecular tools to determine the neural pathways relevant to different aspects of cognition, and to manipulate glutamate transmission at the neuron-astrocyte intersection, in order to gain more specific understanding of the contribution of the tripartite synapse to cognitive function. Ultimately, we hope that these efforts will contribute to better understanding of the association between different cognitive domains and psychosis, and to the development of novel treatment venues.

(2) epigenetic mechanisms underlying the impact of stress on behavior.

Epigenetic changes (i.e. inheritable, functionally-relevant modifications in the genome that do not involve the DNA sequence) can mediate the environment’s influence on brain function and behavioral output. For example, we and others have shown that environmental stress, particularly in adolescence, leads to epigenetic modifications on the DNA and RNA levels . We are interested in unveiling the mechanism by which epigenetic changes modify behavioral output, particularly in the cognitive domain, and in the role epigenetic changes play in gene x environment interactions.

Another line of studies in our lab focuses on the role of epigenetics in the transmission of environmental effects across generations. We have shown that stress to adolescent female rats affects the behavior of their children (F1) and grandchildren (F2), as well as their and their offspring’s gene expression patterns and cortical micro-structure. We have also shown that inter- and trans-generational transmission of stress is likely to involve epigenetic processes in brain and germ cells, and that individual behavior is affected by personal as well as parental exposure to environmental influences. Ultimately, we aim to understand the mechanism by which experience is transmitted to future generations, and the role it plays in their adaptability to changing environmental demands.