Yukiori Goto

Regulation of firing of dopaminergic neurons and control of goal-directed behaviors

There are several brain regions that have been implicated in the control of motivated behavior and whose disruption leads to the pathophysiology observed in major psychiatric disorders. These systems include the ventral hippocampus, which is involved in context and focus on tasks, the amygdala, which mediates emotional behavior, and the prefrontal cortex, which modulates activity throughout the limbic system to enable behavioral flexibility. Each of these systems has overlapping projections to the nucleus accumbens, where these inputs are integrated under the modulatory influence of dopamine. Here, we provide a systems-oriented approach to interpreting the function of the dopamine system, its modulation of limbic-cortical interactions and how disruptions within this system might underlie the pathophysiology of schizophrenia and drug abuse.

Dopaminergic modulation of limbic and cortical drive of nucleus accumbens in goal-directed behavior.

Goal-directed behavior is believed to involve interactions of prefrontal cortical and limbic inputs in the nucleus accumbens (NAcc), and their modulation by mesolimbic dopamine (DA) seems to be of primary importance in NAcc function. Using in vivo electrophysiological recordings simultaneously with DA system manipulation in rats, we show that tonic and phasic DA release selectively modulates hippocampal and prefrontal cortical inputs through D1 and D2 receptors, respectively. In addition, we also found that D1 activation and D2 inactivation in the NAcc produced behaviorally selective effects (learning versus set shifting of response strategy) that correspond to specific afferents. These results suggest that the dynamics of DA release regulate the balance between limbic and cortical drive through activation and inactivation of DA receptor subtypes in the accumbens, and this regulates goal-directed behavior.

The Yin and Yang of dopamine release: a new perspective.

Dopamine has undergone extensive investigation due to its known involvement in a number of neurological and psychiatric disorders. In particular, studies into pathological conditions have focused on the roles of high amplitude, phasically evoked dopamine release in regions such as the prefrontal cortex and striatum. However, research has shown that dopamine release can be more complex than just phasic release; thus, there is also a tonic, background dopamine release, with alterations in tonic dopamine release likely having unique and important functional roles. Unfortunately, however, tonic dopamine release has received relatively little attention. In this review, we summarize our recent studies and discuss how modulation of the dopamine system, both in terms of phasic activation and attenuation of tonic dopamine are important for the functions of brain regions receiving this dopamine innervation, and that imbalances in these dopamine release mechanisms may play a significant role in psychiatric disorders such as schizophrenia.

Limbic and cortical information processing in the nucleus accumbens

The nucleus accumbens regulates goal-directed behaviors by integrating information from limbic structures and the prefrontal cortex. Here, we review recent studies in an attempt to provide an integrated view of the control of information processing in the nucleus accumbens in terms of the regulation of goal-directed behaviors and how disruption of these functions might underlie the pathological states in drug addiction and other psychiatric disorders. We propose a model that could account for the results of several studies investigating limbic-system interactions in the nucleus accumbens and their modulation by dopamine and provide testable hypotheses for how these might relate to the pathophysiology of major psychiatric disorders.

Functional and Dysfunctional Synaptic Plasticity in Prefrontal Cortex: Roles in Psychiatric Disorders

Prefrontal cortex (PFC) mediates an assortment of cognitive functions including working memory, behavioral flexibility, attention, and future planning. Unlike the hippocampus, where induction of synaptic plasticity in the network is well-documented in relation to long-term memory, cognitive functions mediated by the PFC have been thought to be independent of long-lasting neuronal adaptation of the network. Nonetheless, accumulating evidence suggests that prefrontal cortical neurons possess the cellular machinery of synaptic plasticity and exhibit lasting changes of neural activity associated with various cognitive processes. Moreover, deficits in the mechanisms of synaptic plasticity induction in the PFC might be involved in the pathophysiology of psychiatric and neurological disorders such as schizophrenia, drug addiction, mood disorders, and Alzheimers disease.

Dopamine-dependent interactions between limbic and prefrontal cortical plasticity in the nucleus accumbens: disruption by cocaine sensitization.

The prefrontal cortex and the hippocampus exhibit converging projections to the nucleus accumbens and have functional reciprocal connections via indirect pathways. As a result, information processing between these structures is likely to be bidirectional. Using evoked potential measures, we examined the interactions of these inputs on synaptic plasticity within the accumbens. Our results show that the direction of information flow between the prefrontal cortex and limbic structures determines the synaptic plasticity that these inputs exhibit within the accumbens. Moreover, this synaptic plasticity at hippocampal and prefrontal inputs selectively involves dopamine D1 and D2 activation or inactivation, respectively. Repeated cocaine administration disrupted this synaptic plasticity at hippocampal and prefrontal cortical inputs and goal-directed behavior in the spatial maze task. Thus, interactions of limbic-prefrontal cortical synaptic plasticity and its dysfunction within the accumbens could underlie complex information processing deficits observed in individuals following psychostimulant administration.

The dopamine system and the pathophysiology of schizophrenia: a basic science perspective.

The dopamine system has been a subject of intense investigation due to its role in a number of normal functions and its disruption in pathological conditions. Thus, the dopamine system has been shown to play a major role in cognitive, affective, and motor functions, and its disruption has been proposed to underlie the pathophysiology of several major psychiatric and neurological disorders, including schizophrenia, Parkinsons disease, drug abuse, and attention deficit/hyperactivity disorder. Although these studies have continued to define the basic functional principles of the dopamine system in the mammalian brain, we are still at the initial stages in unraveling the complex role of this transmitter system in regulating behavioral processes. Accumulating evidence suggests that dopamine modulates excitatory and inhibitory neurotransmission, and moreover affects synaptic plasticity induced within the circuits of its target brain regions. It is this role in synaptic plasticity that has associated the dopamine system with aspects of cognitive function involving learning and memory. In this chapter, we summarize recent findings relevant to the role of the dopamine system in psychiatric disorders at cellular, anatomical, and functional levels. In particular, we will focus on the regulation of dopamine neuron activity states and how this impacts dopamine release in cortical and subcortical systems, and the physiological and behavioral impact of dopamine receptor stimulation in the postsynaptic targets of these neurons. A brief summary of recent findings regarding the development and maturation of DA system and how this relates to the pathophysiology of psychiatric disorders are given, and finally models of dopamine system disruption in schizophrenia and how therapeutic approaches impact on dopamine system dynamics is presented.

Alterations in medial prefrontal cortical activity and plasticity in rats with disruption of cortical development.

BACKGROUND Psychiatric disorders such as schizophrenia are believed to emerge from an interaction of several factors. Thus, a genetic predisposition can lead to developmental compromises that may leave the system more susceptible to deficits induced by subsequent environmental variables such as stress. METHODS The impact of neurodevelopmental interruption induced by exposure of rats prenatally to a compound methylazoxymethanol acetate (MAM) that disrupts neuronal proliferation was investigated using in vivo electrophysiologic recordings from the prefrontal cortex of adult rats. RESULTS Prenatal exposure to MAM resulted in alterations in the medial prefrontal cortex indicative of a compromise in information processing. Specifically, we observed a disruption in activity patterns consistent with deficits in neuronal synchronization and abnormal augmentation of synaptic plasticity that was more severely disrupted by stress exposure than in normal animals. Furthermore, these deficits could be reversed by manipulating the mesocortical dopamine system. CONCLUSIONS These results suggest that disruption of early cortical development causes impairments in medial prefrontal cortical function at adulthood that are more vulnerable to disruptive influences, despite the presence of only subtle structural alterations in the brain.

Timing-dependent limbic-motor synaptic integration in the nucleus accumbens

The nucleus accumbens is a brain region in which limbic and motor inputs converge. How these information modalities shape accumbens output is not clearly understood. Here, we report that synaptic inputs from the prefrontal cortex and limbic structures interact differently depending on their timing. Coincident inputs may result in enhancing information flow through the nucleus accumbens. Responses to asynchronous inputs are affected by their relative order of arrival, with limbic inputs allowing subsequent prefrontal responses, and prefrontal inputs dampening limbic responses. These mechanisms allow for both coincidence detection and input selection in this integrative brain region.

Prefrontal Lesion Reverses Abnormal Mesoaccumbens Response in an Animal Model of Schizophrenia

BACKGROUND A neonatal hippocampal lesion induces postpubertal behavioral alterations resembling phenomena observed in schizophrenia. We have recently reported that nucleus accumbens neurons exhibit altered response to ventral tegmental area activation, but only when animals with this lesion reach adulthood. Because a prefrontal cortical lesion eliminates postpubertal abnormal behaviors in these animals, we investigated whether altered accumbens responses were reversed with this manipulation. METHODS In vivo intracellular recordings were conducted in accumbens neurons in rats that had received neonatal hippocampal lesions combined with either adult prefrontal cortical lesion or sham treatment. Accumbens response to mesolimbic pathway activation was recorded in these animals. RESULTS Accumbens neurons from animals with a neonatal hippocampal lesion and an adult prefrontal sham operation still showed altered accumbens response to mesolimbic stimulation. On the other hand, most animals with combined neonatal hippocampal and adult prefrontal lesions exhibited responses similar to those of naïve animals. CONCLUSIONS This result suggests that abnormal behaviors in these animals might be related to excessive prefrontal drive of accumbens neurons upon dopamine activation.