[R21] Psychedelic neuroplastogen rescue of cognitive flexibily in autism spectrum disorder
Ente: National Institute of Mental Health
Scadenza: 2028-07-31
Importo max: 429.000 EUR
Paese: US
Descrizione
PROJECT SUMMARY / ABSTRACT
Increasing numbers of people, including adults, have been diagnosed with autism spectrum disorder (ASD).
For people utilizing medications for ASD, results are often unsatisfactory and involve off-target effects,
necessitating the identification of better treatments. This project will help address this significant gap in
knowledge by investigating the ability of psychedelic drugs to normalize cognitive flexibility deficits and
changes to prefrontal cortex circuits caused by Cntnap2 knockout (KO), a mouse model that captures some of
the behavioral abnormalities associated with ASD, including cognitive rigidity.
Cognitive flexibility, a fundamental process that is required for adaptive behavior, is compromised in many
people with ASD. As the PFC is important for cognitive flexibility and control of behavior, ASD-related cognitive
inflexibility may be correlated with the known alterations to density of dendritic spines, a proxy for synaptic
connectivity, in prefrontal cortex pyramidal neurons. Similarly, decreases in cognitive flexibility, reductions in
dendritic spine density, and attenuations in excitatory synaptic input to PFC pyramidal neurons have been
reported in mouse models that capture ASD-associated behavioral phenotypes. In contrast, psychedelic
treatment has been shown to improve cognitive flexibility, elevate dendritic spine density, and boost excitatory
synaptic input to PFC pyramidal cells. Therefore, psychedelic-mediated repair of PFC circuits and associated
flexible behaviors may represent a novel ASD treatment paradigm.
Although psychedelic treatment is a promising target for both increasing reversal learning ability and enhancing
PFC synaptic connectivity in people with major depression, it is unknown if psychedelic treatment is able to
normalize cognitive flexibility alterations and repair neural circuits disrupted in ASD, leaving a critical
unaddressed question. Here, using long-time scale behavioral measures of flexibility and synaptic
morphophysiological analyses, we will test the central hypothesis that psychedelic treatment will improve
reversal learning ability (Aim 1) and repair PFC circuit structure and function (Aim 2) that is compromised in the
Cntnap2 KO mice. Successful completion of these aims has the potential to significantly improve our
understanding of the utility of psychedelic medicine for the treatment of ASD, as this treatment paradigm holds
the promise of improving flexible learning by fundamentally changing the underlying synaptic landscape in
PFC.
Istituzione: UNIVERSITY OF MICHIGAN AT ANN ARBOR
PI: Omar Jamil Ahmed
Progetto: 1R21MH144686-01
Settori: National Institute of Mental Health
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