Patricio O’Donnell

Ensemble coding in the nucleus accumbens

The nucleus accumbens may be involved in cognitive functions via its control of thalamocortical activity feeding back to the prefrontal cortex. Functional neuronal ensembles, or changes in the spatial and temporal distribution of active and inactive neurons, may mediate information processing in the accumbens. Neurons are considered active during the plateau depolarizations, or up state, that most nucleus accumbens neurons exhibit. Action potential firing can occur only during these events in these neurons. Inputs controlling the distribution and timing of up events (i.e., limbic afferents and dopamine) may determine the spatiotemporal pattern of accumbens neuronal ensembles and, therefore, of thalamoprefrontal cortical activity.

Altered Prefrontal Cortical Metabolic Response to Mesocortical Activation in Adult Animals with a Neonatal Ventral Hippocampal Lesion

BACKGROUND Adult animals with a neonatal ventral hippocampal lesion (NVHL) exhibit deficits in working memory and sensorimotor gating similar to those observed in schizophrenia. As cognitive deficits in this disorder are typically associated with changes in cortical metabolic levels, we investigated here whether an NVHL affects metabolic responses to ventral tegmental area (VTA) activation, a procedure that elicits abnormal cell firing in the prefrontal cortex (PFC) of NVHL animals. METHODS Prefrontal cortex metabolic activity was determined by measuring cytochrome oxidase I (CO-I) staining. Cytochrome oxidase I levels were quantified by densitometry in pre- and postpubertal sham-operated and lesioned rats that received one or three series of fifteen 20-Hz trains of VTA stimuli every 20 seconds. RESULTS Ventral tegmental area stimulation yielded higher levels of PFC CO-I in NVHL animals when compared with the sham-operated group, an effect that appeared only after puberty. Increasing the series of burst stimulations further elevated CO-I in sham-operated, but not in NVHL animals. CONCLUSIONS Increased PFC CO-I activity after VTA burst stimulation in NVHL rats highlights the enhanced energy demand that could be linked to the exaggerated response to stress observed in these animals. The inability to further increase the response with higher mesocortical activity, as observed in sham-operated animals, could be expression of a reduced PFC functional capacity in lesioned animals. Thus, a hyperexcitable PFC with a reduced ability to further increase activity could be a plausible pathophysiological scenario for schizophrenia. Human functional studies could be interpreted in the light of this conceptual framework.

Social Isolation Rearing Affects Prefrontal Cortical Response to Ventral Tegmental Area Stimulation

BACKGROUND Animals reared in social isolation exhibit attentional deficits that parallel those found in schizophrenia patients. Such disturbances are frequently attributed to a dysfunction of the mesocortical system. Here we investigated whether electrophysiologic characteristics of prefrontal cortical pyramidal neurons or mesocortical responses were changed in isolated animals. METHODS In vivo intracellular recordings were obtained from prefrontal cortical pyramidal neurons in animals raised in social isolation or in socialized control animals before and after ventral tegmental area stimulation mimicking dopamine cell burst firing. RESULTS Prefrontal cortical pyramidal neurons recorded from isolated animals showed bimodal characteristics resembling those of their socialized littermates. Stimulation of the ventral tegmental area evoked plateau depolarizations in both groups, but this was accompanied by abnormal firing or a short hyperpolarization in most of the isolated animals. CONCLUSION These findings suggest that social isolation rearing may affect mesocortical information processing.

BrainSeq: Neurogenomics to Drive Novel Target Discovery for Neuropsychiatric Disorders

We outline an ambitious project to characterize the genetic and epigenetic regulation of multiple facets of transcription in distinct brain regions across the human lifespan in samples of major neuropsychiatric disorders and controls. Initially focused on schizophrenia and mood disorders, the goal of this consortium is to elucidate the underlying molecular mechanisms of genetic associations with the goal of identifying novel therapeutic targets. The consortium currently consists of seven pharmaceutical companies and a not-for-profit medical research institution working as a precompetitive team to generate and analyze publicly available archival brain genomic data related to neuropsychiatric illness.

Dopamine Modulation of Prefrontal Cortical Neural Ensembles and Synaptic Plasticity

The prefrontal cortex has been implicated in executive functions, and it can become dysfunctional in psychiatric disorders such as schizophrenia. Prefrontal pyramidal neurons exhibit dynamic membrane potential activity in vivo, which depends on local microcircuits and synaptic inputs from other brain structures and may define neural ensembles encoding information. Mesocortical dopamine modulates these membrane potential states, allowing for long-term synaptic plasticity in the prefrontal cortex. Dopamine-mediated ensemble coding reinforcement may therefore be important for associative learning and executive functions. Dysfunction of associative learning and neural plasticity induced by dopamine abnormalities in the prefrontal cortex may be central components in the pathophysiology of schizophrenia.

Dopamine and Ensemble Coding in the Striatum and Nucleus Accumbens

Most medium spiny neurons in the striatum and nucleus accumbens exhibit spontaneous alternations in their membrane potential when recorded intracellularly in vivo. A very negative resting potential (down state) is periodically interrupted by plateau depolarizations that bring the membrane potential close to firing threshold (up state). Action potential firing can only be observed during the up state. The spatial distribution of neurons in their up state at any given moment may represent an ensemble that controls the disinhibition of a set of thalamocortical units. The modulation of transitions between states may therefore have an impact on information processing within basal ganglia circuits. The actions of dopamine in the basal ganglia have been studied mostly with a focus on whether it is an excitatory or inhibitory agent, but the diversity of receptor subtypes, behavioral responses, and electrophysiological actions has precluded a conclusive view of the overall effect of dopamine cell activation. Following M. Levine’s recent work showing that D1 receptors may enhance NMDA-mediated responses and D2 receptors may reduce AMPA responses, we propose that DA may act by stabilizing the membrane potential state in target neurons (either up or down). Dopamine cells fire en bloc in the presence of behaviorally relevant stimuli, resulting in a massive release of dopamine in target areas that may “tag” the distribution of active and inactive neurons. Therefore, dopamine may reinforce the ongoing ensemble, in a coincidence detection mechanism that requires glutamatergic inputs and dopamine.

Hippocampal Regulation of Prefrontal Cortex — Nucleus Accumbens Information Processing

Early electrophysiological studies have suggested that information in the brain may be encoded by the activity of distributed networks (assemblies) of neurons (Hebb 1949; Kristan and Gerstein 1970; Eccles 1971). This was validated by recently developed multichannel recording in behaving animals (Wilson and McNaughton 1993; Deadwyler et al. 1996; Nicolelis et al. 1997). Early neural network models such as theparallel distributed processing(Rummelhart and McClelland 1986) have also relied on neural ensembles. One assumption of “ensemble coding” models is that activity in a distributed set of neurons may be coordinated or synchronized by an external source or “teacher”. In most experimental settings, however, such synchronization has either been elusive or, in the best cases, weak (Chang et al. 2000). Multichannel recordings typically rely on spike firing. Perhaps ensembles of active neurons are not defined by instantaneous action potential synchronization, but by whether cells are firing or not during a physiologically relevant period. If this is the case, subthreshold events, which are driven by afferent inputs and intrinsic currents, may be a better measure to study neural assemblies (O’Donnell 1999).In vivointracellular recordings from nucleus accumbens (NAC) and dorsal striatal neurons in anesthetized animals have revealed a bistable membrane potential (Wilson 1993; Leung and Yim 1993; O’Donnell and Grace 1995; Goto and O’Donnell 2001b). A very negative resting membrane potential (DOWN state) is periodically interrupted by plateau depolarizations (UP state). If neural ensembles in the NAC were defined by a network of neurons in a depolarized membrane potential state, a population recording method such as local field potentials (LFPs) would be a better also decreases the response to afferent activation. The latter also includes responses to PFC stimulation, bothin vitro(O’Donnell and Grace 1994) andin vivo(Himmelheber and O’Donnell 2001).