SUMMARY – OVERALL
A major goal of NIMH is to understand the neurobiology underlying common cognitive and behavioral deficits
associated with mental disorders. Such behavioral deficits, as well as action plans executed in response to
novel sensory experiences, are gated by cognitive processing within neocortical circuits. It is expected that
a mechanistic and multi-level biological understanding of how cortical circuits are built and refined during
development will reveal molecular targets for future therapeutic strategies to treat mental disorders. Thus,
the goal of this Center is to understand how gene expression and associated gene function within key
neuronal subtypes regulates neurobiological substrates required to form cortical circuits that enable
decision-making and behavioral adaptations. A Conte Center will provide rapid and efficient bidirectional
flow of information and tools, as well as synergy and integration that could not be achieved using individual
grants. Ras and Rho-like small GTPases play fundamental biological roles within neurons by controlling cell-
autonomous growth-related signaling pathways and orchestrating neuronal circuit assembly and function.
GEFs and GAPs are direct upstream regulators of small GTPase signaling, and within neurons, orchestrate
cellular migration, neuronal morphogenesis, synaptic connectivity, synaptic plasticity triggered in response
to novel sensory experience, in vivo neural circuit function, and associated behavioral adaptations. GEFs
and GAPs as exemplar biological entry points for understanding how cellular GTPase signaling shapes
neural circuits that facilitate adaptive behaviors. However, it is unknown how their expression and function
within specific neuronal subtypes and defined developmental windows drive cortical circuit refinement to
impact cognitive processing and associated behaviors. To close this knowledge gap, our team is proposing
an integrated, interdisciplinary, multi-level “Center for GTPase Regulation of Neuronal Cell Biology and
Behavior” to study the roles of GTPase signaling in cortical neural circuit with the goal of understanding
fundamental principles that drive the hierarchical organization of brain circuits that underlie complex
behaviors. Comprised of investigators with expertise that spans all major levels of brain function – molecular,
synaptic, cellular, circuit, system, and behavior – the Impact of our Center will be to mechanistically connect
the regulation of GTPase signaling within distinct neuronal subtypes to the assembly and function of
behavioral circuits associated with mental disorders.