Cellular, Behavioral, and Computational Investigations of Dopamine Modulation of Prefrontal Cortical Networks Jeremy Seamans

Schizophrenic Syndrome Positive Symptoms (delusions, hallucinations, disorganized speech, and grossly disorganized or abnormal thinking and behavior) Negative Symptoms (affective flattening, alogia, and avolition, social withdrawl) Cognitive Symptoms (distractability, loss of flexible control of behavior). “Cognitive impairment in schizophrenia is the core of the disorder.” -Elvevag & Goldberg 2000 “Long term prognosis for individuals with schizophrenia appears to be best predicted, not by the severity of positive symptoms, but the degree of cognitive impairment” -Lewis & Lieberman 2000

Schizophrenic Syndrome=Attentional Syndrome As early as the 1900s Kraeplin noted that the more debilitating symptoms of schizophrenia, are disturbances in attention and cognition “Attentional deficits in schizophrenia may be a principal cause of various deficits in higher order cognitive functions...Distractability interferes with the organizational aspects of memory” -Kenny & Meltzer 1991 “Schizophrenic patients present deficits...which depend on the executive attention network.” -Fuentes 2001 Cognitive Symptoms = Dysfunction of executive attention (flexible control of behavior). Positive Symptoms - Dysfunction of attention within thought/perception Negative Symptoms - Dysfunction of emotional attention.

The Prefrontal/Dopamine link Altered release proteins, interneuron as well as altered dopamine receptor function in the prefrontal cortex (PFC) of schizophrenics. Patients with PFC damage exhibit similar problems to schizophrenics Schizophrenics are unable to activate PFC on cognitive tasks This inactivity can be reversed by a dopamine agonist D2 receptor affinity REQUIRED for antipsychotic efficacy while dopamine agonists can induce psychotic symptoms Clozapine produces high levels of D2 occupancy in cortex (relative to striatum) while chronic treatment upregulates cortical D2 receptors and downregulates D1 receptors. Clozapine and other antipsychotics upregulate cortical dopamine turnover. Therefore schizophrenics exhibit a dysfunction in PFC dopamine systems that can be reversed by antipsychotics

How does dopamine regulate network representations in PFC? Behavioral approach: What is dopamine doing functionally? Electrophysiological approach: What are the mechanisms involved in this dopamine regulation? Computational approach: How do the mechanisms relate to function?

Behavioral analyses of dopamine regulation of PFC dependent cognitive processes

Adapted from: Sawaguchi et al. (1986; 1988; 1990a,b)

Dopamine regulation of PFC neurons: Physiological action of dopamine in vitro

Summary of the Physiological Effects of Dopamine

D1 receptor activation enhances evoked firing by shifting I NAP activation

D1 receptor activation increases NMDA EPSCs selectively

Dopamine has bi-directional effects on IPSCs D2D1

D2-mediated reduction of IPSCs is blocked by a muscarinic acetylcholine antagonist (Atropine)

Summary of the Physiological Effects of Dopamine

Linking cellular mechanisms to the functions of dopamine in the PFC Computational Modeling (Daniel Durstewitz)

Simulation of D1 effects leads to reduction in spontaneous but large enhancement in evoked “delay-period” activity

Supervisors Anthony Phillips (UBC) Charles Yang (UBC, Lilly Research Labs. ) Natalia Gorelova (UBC) Terry Sejnowski (Salk Institute) Charles Stevens (Salk Institute) Collaborators Stan Floresco (UBC) Daniel Durstewitz (Salk Institute)