“Fronto-sensory circuit mechanisms of perceptual novelty processing“, NIMH R00-MH115082, PI: J.P. Hamm ($250,000/year total)
“Mapping the role of basal forebrain projections to visual cortex in novelty processing”, Whitehall Foundation, PI: J.P. Hamm ($75,000/year direct)
Project 1: Disorganization of cortical ensembles as a common pathophysiology in psychotic disease.
In layer 2/3 of the cerebral cortex, neurons do not fire independently or uniformly, but separate into coherent, coactivating groups or “ensembles”. Neuronal ensembles observed in awake mice during ongoing resting activity also reliably coactivate to visual stimuli, potentially outlining the preferred activity states or “attractors” of the local circuit. The goal of this project is to examine these dynamics and their disruption as a common endpoint of multiple distinct genotypes which carry significant risk for schizophrenia and other psychotic disorders. We will compare and contrast multiple mouse models of genetic risk for schizophrenia (e.g. DISC1, 22q11.2). Further, we seek to understand how altered spine pruning, perineuronal net maturation, and gamma-band synchrony relate to disorganized cortical ensembles, with a focus on neurodevelopmental changes occurring around late-adolescence, the time period when principal schizophrenia symptoms typically manifest.
see: Hamm, J.P., Peterka, D.S., Gogos, J.A., Yuste, R. (2017) Altered cortical ensembles in mouse models of schizophrenia. Neuron. 94, 1, 153–167.
Project 2: Prefrontal, thalamic, and basal forebrain contributions to sensory context processing
Individuals with schizophrenia and other psychotic disorders exhibit abnormalities in basic sensory processing which undermine how they relate and adapt to a changing environment. For example, while aberrant processing of contextually “novel” and “redundant” stimuli in particular predates disease onset and predicts global functioning deficits in patients, these abnormalities are not mechanistically understood. The proposed project harnesses cutting edge optical tools (optogenetics, two-photon calcium imaging) along with dense extracellular electrophysiology to provide a comprehensive understanding of how glutamatergic inpts from the prefrontal cortex vs acetylcholinergic inputs from the basal forebrain modulate sensory cortices at various circuit levels. Special focus will be put on local interneuron subpopulations and interlaminar dynamics within visual and auditory cortices. Results from this project will provide novel insights for future precision treatments of schizophrenia.
see: Hamm, J.P., Yuste, R. (2016). Somatostatin Interneurons Control a Key Component of Mismatch Negativity in Mouse Visual Cortex. Cell Reports. 16, 407–420.