# Project 1

> **NIH NIH P50** · HARVARD UNIVERSITY · 2021 · $384,861

## Abstract

Abstract
Mice – with their short gestation time, lifespan, large litter size, and above all, genetic tractability
–are powerful experimental tools with which to explore mammalian brain development. One
striking example is the reversible disruption of autism risk genes, like Mecp2 or Shank3.
Switching on these genes after the emergence of fullblown phenotypes rescues several motor-
related symptoms, including inertia, abnormal gait, weight, irregular breathing, repetitive
grooming or hind-limb clasping. Instead, other neurological aspects are uncorrected in
adulthood, such as anxiety or motor coordination. Of central relevance to human patients, it
remains unknown to what extent higher cognition is impaired in Shank3 or Mecp2 mutant mice
and whether recovery would also be limited to a critical period. The Hensch project will directly
address sensitive periods and reversibility of dorsomedial prefrontal cortical (dmPFC) functions
using novel behavioral tests of attention, cognitive flexibility and acoustic preference along with
associated physiological measures from relevant areas. Pioneering work in the first phase of the
Conte Center established the pivotal role of particular inhibitory neurons underlying critical
period timing in mouse sensory systems. Parvalbumin (PV+) GABA circuit maturation dictates
both the onset and closure of these windows of circuit refinement. Manipulations of psychiatric
risk factors, such as circadian Clock gene disruption or redox dysregulation, can delay or extend
developmental trajectories by upsetting the vulnerable PV+ component of local circuit
excitatory-inhibitory balance. Recently, Hensch and Feng extended this principle to higher-order
multi-sensory integration (MSI, commonly impaired in patients with autism) in the insular cortex.
Shared MSI impairments in mice lacking either Shank3 (weak PV+) or Mecp2 (excessive PV+)
suggest an optimal range of PV+ network function enables proper pruning of connections in the
insula. Here, we will examine circuit physiology and anatomy before/after restoration of Shank3
or Mecp2 in mice, ultimately by full 3D EM circuit reconstruction with Lichtman also in
marmosets carrying the same Shank3 deletion (from Feng). Further, our touchscreen two-
choice visual attention assay, a multiple-choice foraging task to assess flexible rule learning,
and preference for acoustic stimuli (music, ultrasonic calls) experienced early in life will probe
dmPFC function in mutant and rescued mice. Electrophysiological recording and two-photon
Calcium / Chloride imaging from the dmPFC in vivo will focus on PV+ networks in these areas
across development, starting with comparison to Arlotta’s human organoids. Based on these
many insights from mice, the impact of silencing/activating PV+ circuits in corresponding frontal
cortical regions of PV-Cre marmosets (by Feng) using focal injections of viral DREADD
constructs can be tested on analogous primate tasks of attention, cognitive flexibility and
pre...

## Key facts

- **NIH application ID:** 10145781
- **Project number:** 5P50MH094271-09
- **Recipient organization:** HARVARD UNIVERSITY
- **Principal Investigator:** Takao K Hensch
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,861
- **Award type:** 5
- **Project period:** 2011-09-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145781

## Citation

> US National Institutes of Health, RePORTER application 10145781, Project 1 (5P50MH094271-09). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10145781. Licensed CC0.

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