Not listed
TRANSLATIONAL STUDIES IN HUMANS AND MICE TO TEST A CIRCUIT-LEVEL COMPUTATIONAL MODEL OF AUDITORY HALLUCINATIONS.. - AUDITORY HALLUCINATIONS (AH) ARE CORE SYMPTOMS OF PSYCHOSIS FOR WHICH TREATMENT IS OFTEN INEFFECTIVE OR POORLY TOLERATED. A FIRST STEP TOWARDS DEVELOPING MORE SELECTIVE AND SAFER BIOLOGICAL INTERVENTIONS IS TO ELUCIDATE AH MECHANISMS AT A NEUROBIOLOGICAL CIRCUIT LEVEL, A LEVEL AT WHICH AH ARE CURRENTLY POORLY UNDERSTOOD. HERE, WE USE A NOVEL COMPUTATIONAL CIRCUIT-LEVEL MODEL COMBINED WITH TRANSLATIONAL EXPERIMENTS IN HUMANS AND MICE TO IDENTIFY CIRCUIT MECHANISMS UNDERLYING AH. DORSAL-STRIATAL DOPAMINE (DA) EXCESS IS IMPLICATED IN AH, AND AH SEVERITY CORRELATES WITH A TASK BEHAVIORAL PHENOTYPE CONSISTING OF INCREASED FALSE ALARMS (ENDORSING AUDITORY SOUNDS THAT ARE NOT PRESENT IN SIGNAL-DETECTION TASKS) REPORTED WITH HIGH CONFIDENCE. IN MICE, STIMULATING DA RELEASE IN THE DORSAL STRIATUM ALSO INDUCES THIS AH-LIKE PHENOTYPE OF HIGH-CONFIDENCE FALSE ALARMS IN A SIMILAR SIGNAL-DETECTION TASK. THESE FINDINGS ARE CONSISTENT WITH COMPUTATIONAL MODELS WHEREBY AH RESULT FROM EXAGGERATED PERCEPTUAL PRIOR EXPECTATIONS AND SUGGEST A ROLE FOR THEIR IMPLEMENTATION IN DORSAL STRIATUM. HOWEVER, THE PRECISE RELATIONSHIPS BETWEEN MODEL-PROPOSED COGNITIVE COMPUTATIONS AND CIRCUIT NEUROBIOLOGY ARE UNCLEAR. IMPORTANT GAPS INCLUDE HOW DORSAL-STRIATAL DA AND MEDIUM SPINY NEURON ACTIVITY CONTRIBUTE TO PERCEPTUAL LEARNING AND AH-LIKE PERCEPTS, AS WELL AS POTENTIAL ADDITIONAL ROLES OF REWARD-BASED PROCESSES IN VENTRAL STRIATUM. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A FIRST-OF-ITS-KIND COMPUTATIONAL CORTICOSTRIATAL CIRCUIT MODEL OF AH WHICH RECAPITULATES DOCUMENTED BEHAVIORAL AND NEURAL PHENOTYPES ASSOCIATED WITH PERCEPTUAL AND REWARD TASKS, AND WHICH ADDITIONALLY GENERATES DA-DEPENDENT AH-LIKE FALSE ALARMS. INFORMED BY THIS MODEL, HERE WE WILL USE HUMAN DATA FROM ANTIPSYCHOTIC-FREE PATIENTS WITH SCHIZOPHRENIA (AIM 1) AND MOUSE DATA INCLUDING A MOUSE MODEL OF GENETIC RISK FOR SCHIZOPHRENIA (AIM 2), COMBINED WITH A TRANSLATIONAL SIGNAL-DETECTION PARADIGM, TO TEST QUANTITATIVE PREDICTIONS FROM OUR AH CIRCUIT MODEL. AIM 1 (HUMANS) WILL USE BEHAVIOR, FMRI AND NEUROMELANIN-SENSITIVE MRI TO TEST FOR DISTINCT CONTRIBUTIONS OF PERCEPTUAL LEARNING TO AH AND THEIR IMPLEMENTATION BY DORSAL-STRIATAL CIRCUITS AND DOPAMINERGIC NIGRAL REGIONS INNERVATING DORSAL STRIATUM. AIM 2 (MICE) WILL USE DA SENSORS, NEURONAL RECORDINGS, AND OPTOGENETIC STIMULATION TO PARSE THE SPECIFIC CONTRIBUTIONS OF DORSAL AND VENTRAL-STRIATAL DA AND MEDIUM SPINY NEURONS TO PERCEPTUAL LEARNING AND AH-LIKE FALSE ALARMS. EXPLORATORY AIM 3 WILL DEVELOP CIRCUIT-MODEL EXTENSIONS INCORPORATING ADDITIONAL CIRCUIT ELEMENTS (E.G., DIRECT D1 AND INDIRECT D2 PATHWAYS, CHOLINERGIC INTERNEURONS) TO HELP FURTHER EXPLAIN CIRCUIT MECHANISMS OF EXISTING D2 AND CANDIDATE NON-D2 ANTIPSYCHOTIC DRUGS. THIS MULTIDISCIPLINARY PROJECT WILL THUS USE TRANSLATIONAL AND COMPUTATIONAL METHODS COMBINING THE STRENGTHS OF CLINICAL AND PRECLINICAL RESEARCH, AND OF THEORY- AND DATA-DRIVEN METHODS, TO ADVANCE OUR KNOWLEDGE ABOUT CIRCUIT MECHANISMS OF PSYCHOSIS. BY OUTLINING CIRCUIT-LEVEL DOPAMINERGIC AND NON-DOPAMINERGIC TARGETS, IT WILL FURTHER PAVE THE WAY FOR DEVELOPING NOVEL TREATMENT APPROACHES WITH ENHANCED SELECTIVITY AND TOLERABILITY.
$839.0k 12/20/24 Not listed
TRANSLATIONAL STUDIES IN HUMANS AND MICE TO TEST A CIRCUIT-LEVEL COMPUTATIONAL MODEL OF AUDITORY HALLUCINATIONS.. - AUDITORY HALLUCINATIONS (AH) ARE CORE SYMPTOMS OF PSYCHOSIS FOR WHICH TREATMENT IS OFTEN INEFFECTIVE OR POORLY TOLERATED. A FIRST STEP TOWARDS DEVELOPING MORE SELECTIVE AND SAFER BIOLOGICAL INTERVENTIONS IS TO ELUCIDATE AH MECHANISMS AT A NEUROBIOLOGICAL CIRCUIT LEVEL, A LEVEL AT WHICH AH ARE CURRENTLY POORLY UNDERSTOOD. HERE, WE USE A NOVEL COMPUTATIONAL CIRCUIT-LEVEL MODEL COMBINED WITH TRANSLATIONAL EXPERIMENTS IN HUMANS AND MICE TO IDENTIFY CIRCUIT MECHANISMS UNDERLYING AH. DORSAL-STRIATAL DOPAMINE (DA) EXCESS IS IMPLICATED IN AH, AND AH SEVERITY CORRELATES WITH A TASK BEHAVIORAL PHENOTYPE CONSISTING OF INCREASED FALSE ALARMS (ENDORSING AUDITORY SOUNDS THAT ARE NOT PRESENT IN SIGNAL-DETECTION TASKS) REPORTED WITH HIGH CONFIDENCE. IN MICE, STIMULATING DA RELEASE IN THE DORSAL STRIATUM ALSO INDUCES THIS AH-LIKE PHENOTYPE OF HIGH-CONFIDENCE FALSE ALARMS IN A SIMILAR SIGNAL-DETECTION TASK. THESE FINDINGS ARE CONSISTENT WITH COMPUTATIONAL MODELS WHEREBY AH RESULT FROM EXAGGERATED PERCEPTUAL PRIOR EXPECTATIONS AND SUGGEST A ROLE FOR THEIR IMPLEMENTATION IN DORSAL STRIATUM. HOWEVER, THE PRECISE RELATIONSHIPS BETWEEN MODEL-PROPOSED COGNITIVE COMPUTATIONS AND CIRCUIT NEUROBIOLOGY ARE UNCLEAR. IMPORTANT GAPS INCLUDE HOW DORSAL-STRIATAL DA AND MEDIUM SPINY NEURON ACTIVITY CONTRIBUTE TO PERCEPTUAL LEARNING AND AH-LIKE PERCEPTS, AS WELL AS POTENTIAL ADDITIONAL ROLES OF REWARD-BASED PROCESSES IN VENTRAL STRIATUM. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A FIRST-OF-ITS-KIND COMPUTATIONAL CORTICOSTRIATAL CIRCUIT MODEL OF AH WHICH RECAPITULATES DOCUMENTED BEHAVIORAL AND NEURAL PHENOTYPES ASSOCIATED WITH PERCEPTUAL AND REWARD TASKS, AND WHICH ADDITIONALLY GENERATES DA-DEPENDENT AH-LIKE FALSE ALARMS. INFORMED BY THIS MODEL, HERE WE WILL USE HUMAN DATA FROM ANTIPSYCHOTIC-FREE PATIENTS WITH SCHIZOPHRENIA (AIM 1) AND MOUSE DATA INCLUDING A MOUSE MODEL OF GENETIC RISK FOR SCHIZOPHRENIA (AIM 2), COMBINED WITH A TRANSLATIONAL SIGNAL-DETECTION PARADIGM, TO TEST QUANTITATIVE PREDICTIONS FROM OUR AH CIRCUIT MODEL. AIM 1 (HUMANS) WILL USE BEHAVIOR, FMRI AND NEUROMELANIN-SENSITIVE MRI TO TEST FOR DISTINCT CONTRIBUTIONS OF PERCEPTUAL LEARNING TO AH AND THEIR IMPLEMENTATION BY DORSAL-STRIATAL CIRCUITS AND DOPAMINERGIC NIGRAL REGIONS INNERVATING DORSAL STRIATUM. AIM 2 (MICE) WILL USE DA SENSORS, NEURONAL RECORDINGS, AND OPTOGENETIC STIMULATION TO PARSE THE SPECIFIC CONTRIBUTIONS OF DORSAL AND VENTRAL-STRIATAL DA AND MEDIUM SPINY NEURONS TO PERCEPTUAL LEARNING AND AH-LIKE FALSE ALARMS. EXPLORATORY AIM 3 WILL DEVELOP CIRCUIT-MODEL EXTENSIONS INCORPORATING ADDITIONAL CIRCUIT ELEMENTS (E.G., DIRECT D1 AND INDIRECT D2 PATHWAYS, CHOLINERGIC INTERNEURONS) TO HELP FURTHER EXPLAIN CIRCUIT MECHANISMS OF EXISTING D2 AND CANDIDATE NON-D2 ANTIPSYCHOTIC DRUGS. THIS MULTIDISCIPLINARY PROJECT WILL THUS USE TRANSLATIONAL AND COMPUTATIONAL METHODS COMBINING THE STRENGTHS OF CLINICAL AND PRECLINICAL RESEARCH, AND OF THEORY- AND DATA-DRIVEN METHODS, TO ADVANCE OUR KNOWLEDGE ABOUT CIRCUIT MECHANISMS OF PSYCHOSIS. BY OUTLINING CIRCUIT-LEVEL DOPAMINERGIC AND NON-DOPAMINERGIC TARGETS, IT WILL FURTHER PAVE THE WAY FOR DEVELOPING NOVEL TREATMENT APPROACHES WITH ENHANCED SELECTIVITY AND TOLERABILITY.
($839k) 12/18/24 Not listed
TRANSLATIONAL STUDIES IN HUMANS AND MICE TO TEST A CIRCUIT-LEVEL COMPUTATIONAL MODEL OF AUDITORY HALLUCINATIONS.. - AUDITORY HALLUCINATIONS (AH) ARE CORE SYMPTOMS OF PSYCHOSIS FOR WHICH TREATMENT IS OFTEN INEFFECTIVE OR POORLY TOLERATED. A FIRST STEP TOWARDS DEVELOPING MORE SELECTIVE AND SAFER BIOLOGICAL INTERVENTIONS IS TO ELUCIDATE AH MECHANISMS AT A NEUROBIOLOGICAL CIRCUIT LEVEL, A LEVEL AT WHICH AH ARE CURRENTLY POORLY UNDERSTOOD. HERE, WE USE A NOVEL COMPUTATIONAL CIRCUIT-LEVEL MODEL COMBINED WITH TRANSLATIONAL EXPERIMENTS IN HUMANS AND MICE TO IDENTIFY CIRCUIT MECHANISMS UNDERLYING AH. DORSAL-STRIATAL DOPAMINE (DA) EXCESS IS IMPLICATED IN AH, AND AH SEVERITY CORRELATES WITH A TASK BEHAVIORAL PHENOTYPE CONSISTING OF INCREASED FALSE ALARMS (ENDORSING AUDITORY SOUNDS THAT ARE NOT PRESENT IN SIGNAL-DETECTION TASKS) REPORTED WITH HIGH CONFIDENCE. IN MICE, STIMULATING DA RELEASE IN THE DORSAL STRIATUM ALSO INDUCES THIS AH-LIKE PHENOTYPE OF HIGH-CONFIDENCE FALSE ALARMS IN A SIMILAR SIGNAL-DETECTION TASK. THESE FINDINGS ARE CONSISTENT WITH COMPUTATIONAL MODELS WHEREBY AH RESULT FROM EXAGGERATED PERCEPTUAL PRIOR EXPECTATIONS AND SUGGEST A ROLE FOR THEIR IMPLEMENTATION IN DORSAL STRIATUM. HOWEVER, THE PRECISE RELATIONSHIPS BETWEEN MODEL-PROPOSED COGNITIVE COMPUTATIONS AND CIRCUIT NEUROBIOLOGY ARE UNCLEAR. IMPORTANT GAPS INCLUDE HOW DORSAL-STRIATAL DA AND MEDIUM SPINY NEURON ACTIVITY CONTRIBUTE TO PERCEPTUAL LEARNING AND AH-LIKE PERCEPTS, AS WELL AS POTENTIAL ADDITIONAL ROLES OF REWARD-BASED PROCESSES IN VENTRAL STRIATUM. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A FIRST-OF-ITS-KIND COMPUTATIONAL CORTICOSTRIATAL CIRCUIT MODEL OF AH WHICH RECAPITULATES DOCUMENTED BEHAVIORAL AND NEURAL PHENOTYPES ASSOCIATED WITH PERCEPTUAL AND REWARD TASKS, AND WHICH ADDITIONALLY GENERATES DA-DEPENDENT AH-LIKE FALSE ALARMS. INFORMED BY THIS MODEL, HERE WE WILL USE HUMAN DATA FROM ANTIPSYCHOTIC-FREE PATIENTS WITH SCHIZOPHRENIA (AIM 1) AND MOUSE DATA INCLUDING A MOUSE MODEL OF GENETIC RISK FOR SCHIZOPHRENIA (AIM 2), COMBINED WITH A TRANSLATIONAL SIGNAL-DETECTION PARADIGM, TO TEST QUANTITATIVE PREDICTIONS FROM OUR AH CIRCUIT MODEL. AIM 1 (HUMANS) WILL USE BEHAVIOR, FMRI AND NEUROMELANIN-SENSITIVE MRI TO TEST FOR DISTINCT CONTRIBUTIONS OF PERCEPTUAL LEARNING TO AH AND THEIR IMPLEMENTATION BY DORSAL-STRIATAL CIRCUITS AND DOPAMINERGIC NIGRAL REGIONS INNERVATING DORSAL STRIATUM. AIM 2 (MICE) WILL USE DA SENSORS, NEURONAL RECORDINGS, AND OPTOGENETIC STIMULATION TO PARSE THE SPECIFIC CONTRIBUTIONS OF DORSAL AND VENTRAL-STRIATAL DA AND MEDIUM SPINY NEURONS TO PERCEPTUAL LEARNING AND AH-LIKE FALSE ALARMS. EXPLORATORY AIM 3 WILL DEVELOP CIRCUIT-MODEL EXTENSIONS INCORPORATING ADDITIONAL CIRCUIT ELEMENTS (E.G., DIRECT D1 AND INDIRECT D2 PATHWAYS, CHOLINERGIC INTERNEURONS) TO HELP FURTHER EXPLAIN CIRCUIT MECHANISMS OF EXISTING D2 AND CANDIDATE NON-D2 ANTIPSYCHOTIC DRUGS. THIS MULTIDISCIPLINARY PROJECT WILL THUS USE TRANSLATIONAL AND COMPUTATIONAL METHODS COMBINING THE STRENGTHS OF CLINICAL AND PRECLINICAL RESEARCH, AND OF THEORY- AND DATA-DRIVEN METHODS, TO ADVANCE OUR KNOWLEDGE ABOUT CIRCUIT MECHANISMS OF PSYCHOSIS. BY OUTLINING CIRCUIT-LEVEL DOPAMINERGIC AND NON-DOPAMINERGIC TARGETS, IT WILL FURTHER PAVE THE WAY FOR DEVELOPING NOVEL TREATMENT APPROACHES WITH ENHANCED SELECTIVITY AND TOLERABILITY.
($839k) 12/18/24 Not listed
TRANSLATIONAL STUDIES IN HUMANS AND MICE TO TEST A CIRCUIT-LEVEL COMPUTATIONAL MODEL OF AUDITORY HALLUCINATIONS.. - AUDITORY HALLUCINATIONS (AH) ARE CORE SYMPTOMS OF PSYCHOSIS FOR WHICH TREATMENT IS OFTEN INEFFECTIVE OR POORLY TOLERATED. A FIRST STEP TOWARDS DEVELOPING MORE SELECTIVE AND SAFER BIOLOGICAL INTERVENTIONS IS TO ELUCIDATE AH MECHANISMS AT A NEUROBIOLOGICAL CIRCUIT LEVEL, A LEVEL AT WHICH AH ARE CURRENTLY POORLY UNDERSTOOD. HERE, WE USE A NOVEL COMPUTATIONAL CIRCUIT-LEVEL MODEL COMBINED WITH TRANSLATIONAL EXPERIMENTS IN HUMANS AND MICE TO IDENTIFY CIRCUIT MECHANISMS UNDERLYING AH. DORSAL-STRIATAL DOPAMINE (DA) EXCESS IS IMPLICATED IN AH, AND AH SEVERITY CORRELATES WITH A TASK BEHAVIORAL PHENOTYPE CONSISTING OF INCREASED FALSE ALARMS (ENDORSING AUDITORY SOUNDS THAT ARE NOT PRESENT IN SIGNAL-DETECTION TASKS) REPORTED WITH HIGH CONFIDENCE. IN MICE, STIMULATING DA RELEASE IN THE DORSAL STRIATUM ALSO INDUCES THIS AH-LIKE PHENOTYPE OF HIGH-CONFIDENCE FALSE ALARMS IN A SIMILAR SIGNAL-DETECTION TASK. THESE FINDINGS ARE CONSISTENT WITH COMPUTATIONAL MODELS WHEREBY AH RESULT FROM EXAGGERATED PERCEPTUAL PRIOR EXPECTATIONS AND SUGGEST A ROLE FOR THEIR IMPLEMENTATION IN DORSAL STRIATUM. HOWEVER, THE PRECISE RELATIONSHIPS BETWEEN MODEL-PROPOSED COGNITIVE COMPUTATIONS AND CIRCUIT NEUROBIOLOGY ARE UNCLEAR. IMPORTANT GAPS INCLUDE HOW DORSAL-STRIATAL DA AND MEDIUM SPINY NEURON ACTIVITY CONTRIBUTE TO PERCEPTUAL LEARNING AND AH-LIKE PERCEPTS, AS WELL AS POTENTIAL ADDITIONAL ROLES OF REWARD-BASED PROCESSES IN VENTRAL STRIATUM. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A FIRST-OF-ITS-KIND COMPUTATIONAL CORTICOSTRIATAL CIRCUIT MODEL OF AH WHICH RECAPITULATES DOCUMENTED BEHAVIORAL AND NEURAL PHENOTYPES ASSOCIATED WITH PERCEPTUAL AND REWARD TASKS, AND WHICH ADDITIONALLY GENERATES DA-DEPENDENT AH-LIKE FALSE ALARMS. INFORMED BY THIS MODEL, HERE WE WILL USE HUMAN DATA FROM ANTIPSYCHOTIC-FREE PATIENTS WITH SCHIZOPHRENIA (AIM 1) AND MOUSE DATA INCLUDING A MOUSE MODEL OF GENETIC RISK FOR SCHIZOPHRENIA (AIM 2), COMBINED WITH A TRANSLATIONAL SIGNAL-DETECTION PARADIGM, TO TEST QUANTITATIVE PREDICTIONS FROM OUR AH CIRCUIT MODEL. AIM 1 (HUMANS) WILL USE BEHAVIOR, FMRI AND NEUROMELANIN-SENSITIVE MRI TO TEST FOR DISTINCT CONTRIBUTIONS OF PERCEPTUAL LEARNING TO AH AND THEIR IMPLEMENTATION BY DORSAL-STRIATAL CIRCUITS AND DOPAMINERGIC NIGRAL REGIONS INNERVATING DORSAL STRIATUM. AIM 2 (MICE) WILL USE DA SENSORS, NEURONAL RECORDINGS, AND OPTOGENETIC STIMULATION TO PARSE THE SPECIFIC CONTRIBUTIONS OF DORSAL AND VENTRAL-STRIATAL DA AND MEDIUM SPINY NEURONS TO PERCEPTUAL LEARNING AND AH-LIKE FALSE ALARMS. EXPLORATORY AIM 3 WILL DEVELOP CIRCUIT-MODEL EXTENSIONS INCORPORATING ADDITIONAL CIRCUIT ELEMENTS (E.G., DIRECT D1 AND INDIRECT D2 PATHWAYS, CHOLINERGIC INTERNEURONS) TO HELP FURTHER EXPLAIN CIRCUIT MECHANISMS OF EXISTING D2 AND CANDIDATE NON-D2 ANTIPSYCHOTIC DRUGS. THIS MULTIDISCIPLINARY PROJECT WILL THUS USE TRANSLATIONAL AND COMPUTATIONAL METHODS COMBINING THE STRENGTHS OF CLINICAL AND PRECLINICAL RESEARCH, AND OF THEORY- AND DATA-DRIVEN METHODS, TO ADVANCE OUR KNOWLEDGE ABOUT CIRCUIT MECHANISMS OF PSYCHOSIS. BY OUTLINING CIRCUIT-LEVEL DOPAMINERGIC AND NON-DOPAMINERGIC TARGETS, IT WILL FURTHER PAVE THE WAY FOR DEVELOPING NOVEL TREATMENT APPROACHES WITH ENHANCED SELECTIVITY AND TOLERABILITY.
$0 9/20/24 Not listed
TRANSLATIONAL STUDIES IN HUMANS AND MICE TO TEST A CIRCUIT-LEVEL COMPUTATIONAL MODEL OF AUDITORY HALLUCINATIONS.. - AUDITORY HALLUCINATIONS (AH) ARE CORE SYMPTOMS OF PSYCHOSIS FOR WHICH TREATMENT IS OFTEN INEFFECTIVE OR POORLY TOLERATED. A FIRST STEP TOWARDS DEVELOPING MORE SELECTIVE AND SAFER BIOLOGICAL INTERVENTIONS IS TO ELUCIDATE AH MECHANISMS AT A NEUROBIOLOGICAL CIRCUIT LEVEL, A LEVEL AT WHICH AH ARE CURRENTLY POORLY UNDERSTOOD. HERE, WE USE A NOVEL COMPUTATIONAL CIRCUIT-LEVEL MODEL COMBINED WITH TRANSLATIONAL EXPERIMENTS IN HUMANS AND MICE TO IDENTIFY CIRCUIT MECHANISMS UNDERLYING AH. DORSAL-STRIATAL DOPAMINE (DA) EXCESS IS IMPLICATED IN AH, AND AH SEVERITY CORRELATES WITH A TASK BEHAVIORAL PHENOTYPE CONSISTING OF INCREASED FALSE ALARMS (ENDORSING AUDITORY SOUNDS THAT ARE NOT PRESENT IN SIGNAL-DETECTION TASKS) REPORTED WITH HIGH CONFIDENCE. IN MICE, STIMULATING DA RELEASE IN THE DORSAL STRIATUM ALSO INDUCES THIS AH-LIKE PHENOTYPE OF HIGH-CONFIDENCE FALSE ALARMS IN A SIMILAR SIGNAL-DETECTION TASK. THESE FINDINGS ARE CONSISTENT WITH COMPUTATIONAL MODELS WHEREBY AH RESULT FROM EXAGGERATED PERCEPTUAL PRIOR EXPECTATIONS AND SUGGEST A ROLE FOR THEIR IMPLEMENTATION IN DORSAL STRIATUM. HOWEVER, THE PRECISE RELATIONSHIPS BETWEEN MODEL-PROPOSED COGNITIVE COMPUTATIONS AND CIRCUIT NEUROBIOLOGY ARE UNCLEAR. IMPORTANT GAPS INCLUDE HOW DORSAL-STRIATAL DA AND MEDIUM SPINY NEURON ACTIVITY CONTRIBUTE TO PERCEPTUAL LEARNING AND AH-LIKE PERCEPTS, AS WELL AS POTENTIAL ADDITIONAL ROLES OF REWARD-BASED PROCESSES IN VENTRAL STRIATUM. TO ADDRESS THESE GAPS, WE HAVE DEVELOPED A FIRST-OF-ITS-KIND COMPUTATIONAL CORTICOSTRIATAL CIRCUIT MODEL OF AH WHICH RECAPITULATES DOCUMENTED BEHAVIORAL AND NEURAL PHENOTYPES ASSOCIATED WITH PERCEPTUAL AND REWARD TASKS, AND WHICH ADDITIONALLY GENERATES DA-DEPENDENT AH-LIKE FALSE ALARMS. INFORMED BY THIS MODEL, HERE WE WILL USE HUMAN DATA FROM ANTIPSYCHOTIC-FREE PATIENTS WITH SCHIZOPHRENIA (AIM 1) AND MOUSE DATA INCLUDING A MOUSE MODEL OF GENETIC RISK FOR SCHIZOPHRENIA (AIM 2), COMBINED WITH A TRANSLATIONAL SIGNAL-DETECTION PARADIGM, TO TEST QUANTITATIVE PREDICTIONS FROM OUR AH CIRCUIT MODEL. AIM 1 (HUMANS) WILL USE BEHAVIOR, FMRI AND NEUROMELANIN-SENSITIVE MRI TO TEST FOR DISTINCT CONTRIBUTIONS OF PERCEPTUAL LEARNING TO AH AND THEIR IMPLEMENTATION BY DORSAL-STRIATAL CIRCUITS AND DOPAMINERGIC NIGRAL REGIONS INNERVATING DORSAL STRIATUM. AIM 2 (MICE) WILL USE DA SENSORS, NEURONAL RECORDINGS, AND OPTOGENETIC STIMULATION TO PARSE THE SPECIFIC CONTRIBUTIONS OF DORSAL AND VENTRAL-STRIATAL DA AND MEDIUM SPINY NEURONS TO PERCEPTUAL LEARNING AND AH-LIKE FALSE ALARMS. EXPLORATORY AIM 3 WILL DEVELOP CIRCUIT-MODEL EXTENSIONS INCORPORATING ADDITIONAL CIRCUIT ELEMENTS (E.G., DIRECT D1 AND INDIRECT D2 PATHWAYS, CHOLINERGIC INTERNEURONS) TO HELP FURTHER EXPLAIN CIRCUIT MECHANISMS OF EXISTING D2 AND CANDIDATE NON-D2 ANTIPSYCHOTIC DRUGS. THIS MULTIDISCIPLINARY PROJECT WILL THUS USE TRANSLATIONAL AND COMPUTATIONAL METHODS COMBINING THE STRENGTHS OF CLINICAL AND PRECLINICAL RESEARCH, AND OF THEORY- AND DATA-DRIVEN METHODS, TO ADVANCE OUR KNOWLEDGE ABOUT CIRCUIT MECHANISMS OF PSYCHOSIS. BY OUTLINING CIRCUIT-LEVEL DOPAMINERGIC AND NON-DOPAMINERGIC TARGETS, IT WILL FURTHER PAVE THE WAY FOR DEVELOPING NOVEL TREATMENT APPROACHES WITH ENHANCED SELECTIVITY AND TOLERABILITY.
$0 9/20/24