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Cooperative dysfunction of thalamocortical and cerebellar inputs to the auditory cortex in 22q11.2 deletion syndrome model of schizophrenia.

Award Number: R01MH136215
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Cooperative dysfunction of thalamocortical and cerebellar inputs to the auditory cortex in 22q11.2 deletion syndrome model of schizophrenia. - ABSTRACT Altered neural circuit function most likely underlies schizophrenia (SCZ)-related psychosis. One enigmatic symptom of SCZ is auditory hallucinations, which comprise 85% of all hallucinations in SCZ. The risk of SCZ is 30-fold greater in persons with 22q11.2 deletion syndrome (22q11DS). In murine models of 22q11DS, we showed that the auditory cortex (ACx), which is implicated in auditory hallucinations, has abnormal activities (e.g., sound-like neural ensemble firings during silence) that are rescued by antipsychotics. We also identified 2 brain structures related to auditory perception that are affected in 22q11DS: the auditory thalamus, which fails to send sufficient information about external sensory information to the ACx via thalamocortical (TC) projections, and the paraflocculus (PF), which projects to the ACx but is substantially smaller in people and mice with 22q11DS than in the general population and wild-type (WT) littermates, respectively. We characterized the mechanisms of disrupted glutamatergic transmission at TC projections in 22q11DS mice. Haploinsufficiency of the 22q11DS gene Dgcr8 and upregulation of dopamine receptor Drd2, a target of antipsychotics, mediate this deficit. However, basic knowledge about the PF–ACx circuits and the mechanism of their dysfunction in 22q11DS are unclear. Preliminary data show that Purkinje cells (inhibitory neurons) in the PF fire less in 22q11DS models, causing disinhibition (hyperactivity) of glutamatergic neurons in the deep cerebellar nuclei, the major output of the cerebellum. Thus, imbalanced auditory thalamus–cerebellum interactions may converge onto the ACx and cause abnormal neuronal activity. Our new preliminary data show that the PF reaches the ACx via at least 2 polysynaptic pathways: 1 targets the primary ACx (A1 area) via the lemniscal pathway, and the other targets the secondary ACx (e.g., AuV area) via the nonlemniscal pathway. We also show that PF abnormalities are linked to haploinsufficiency of another 22q11DS gene Tbx1. Here we will test the hypothesis that the dysfunction of PF–auditory circuits and TC circuits underlies abnormal ACx activity in 22q11DS. In Aim 1, we will test if mimicking 22q11DS abnormalities (i.e., reducing thalamic output and increasing cerebellar output) causes abnormal ACx activity in mice. We will also test if enhancing thalamic output and reducing cerebellar output restores ACx activity in 22q11DS mice. For this, we will use the chemogenetics approach. We will also test if the heterozygosity of Dgcr8 and Tbx1 is sufficient to replicate abnormal ACx activity in 22q11DS mice. In Aim 2, we will elucidate and validate the PF–auditory system connectivity in WT and 22q11DS mice to determine if the PF reduction/dysfunction alters inputs to the auditory thalamus and ACx, thereby contributing to abnormal auditory processing. Results of these experiments will suggest a new direction for developing therapeutic interventions by restoring TC communication and reducing abnormal cerebellar activity in those with 22q11DS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $623,312 )
2026	2026	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Mental Health Research Grants	000	2	3/24/2026	NON-COMPETING CONTINUATION	$623,312
														Subtotal = $623,312

Issue Date FY: 2025 ( Subtotal = $731,035 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Mental Health Research Grants	001	1	11/29/2024	NEW	$9,436
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Mental Health Research Grants	000	1	11/27/2024	NEW	$721,599
														Subtotal = $731,035

Grand Total All Awards = $1,354,347

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Cooperative dysfunction of thalamocortical and cerebellar inputs to the auditory cortex in 22q11.2 deletion syndrome model of schizophrenia.

Award Number: R01MH136215

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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