Patricio O'Donnell

Dopamine–Glutamate Interactions Controlling Prefrontal Cortical Pyramidal Cell Excitability Involve Multiple Signaling Mechanisms

Although the importance of dopamine (DA) for prefrontal cortical (PFC) cognitive functions is widely recognized, the nature of DA actions in the PFC remains controversial. A critical component in DA actions is its modulation of glutamate transmission, which can be different when specific receptors are activated. To obtain a clear picture of cellular mechanisms involved in these interactions, we studied the effects of DA–glutamate coactivation on pyramidal cell excitability in brain slices obtained from developmentally mature rats using whole-cell patch-clamp recordings. Bath application of NMDA, AMPA, and the D1 agonist SKF38393 induced concentration-dependent excitability increases, whereas bath application of the D2 receptor agonist quinpirole induced a concentration-dependent excitability decrease. The NMDA-mediated response was potentiated by SKF38393. This NMDA–D1 synergism required postsynaptic intracellular Ca2+ and protein kinase A (PKA) and was independent of membrane depolarization. On the other hand, the excitatory effects of both NMDA and AMPA were attenuated by a D2 agonist. Surprisingly, the D2–NMDA interaction was also blocked by the GABAA antagonists bicuculline and picrotoxin, suggesting that the inhibitory action of D2 receptors on NMDA-induced responses in the PFC may be mediated by GABAergic interneurons. In contrast, the D2–AMPA interaction involves inhibition of PKA and activation of phospholipase lipase C–IP3 and intracellular Ca2+ at a postsynaptic level. Thus, the modulatory actions of D1 and D2 receptors on PFC pyramidal cell excitability are mediated by multiple intracellular mechanisms and by activation of GABAA receptors, depending on the glutamate receptor subtypes involved.

Dopamine gating of forebrain neural ensembles

Dopamine may exert different actions depending on a number of factors. A common view is that D1 receptors may be responsible for excitatory actions whereas D2 receptors are involved in inhibitory actions. However, this position cannot be reconciled with several findings indicating otherwise. The role of dopamine on forebrain neural ensembles may be better understood in the light of functional states of the system. Pyramidal cortical neurons and striatal medium spiny neurons alternate between two membrane potential states (‘up’ and ‘down’) that could shape dopamine actions. It is proposed that D1 receptors can act as state‐stabilizers by sustaining up states and thereby facilitating plasticity mechanisms by providing postsynaptic depolarization and increasing NMDA function. In this way, dopamine can sustain activity in depolarized units. This action is accompanied by a decrease in cell firing (perhaps mediated by D2 receptors), which renders the cells responsive only to strong stimuli. The result would be a net increase in signal‐to‐noise ratio in a selected assembly of neurons.

Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders

Several psychiatric disorders are associated with white matter defects, suggesting that oligodendrocyte (OL) abnormalities underlie some aspects of these diseases. Neuregulin 1 (NRG1) and its receptor, erbB4, are genetically linked with susceptibility to schizophrenia and bipolar disorder. In vitro studies suggest that NRG1-erbB signaling is important for OL development. To test whether erbB signaling contributes to psychiatric disorders by regulating the structure or function of OLs, we analyzed transgenic mice in which erbB signaling is blocked in OLs in vivo. Here we show that loss of erbB signaling leads to changes in OL number and morphology, reduced myelin thickness, and slower conduction velocity in CNS axons. Furthermore, these transgenic mice have increased levels of dopamine receptors and transporters and behavioral alterations consistent with neuropsychiatric disorders. These results indicate that defects in white matter can cause alterations in dopaminergic function and behavior relevant to neuropsychiatric disorders.

Modulation of Cell Firing in the Nucleus Accumbens

ABSTRACT: Pennartz et al. 48 have proposed that functions of the nucleus accumbens (NA) are subserved by the activity of ensembles of neurons rather than by an overall neuronal activation. Indeed, the NA is a site of convergence for a large number of inputs from limbic structures that may modulate the flow of prefrontal cortical information and contribute to defining such ensembles, as exemplified in the ability of hippocampal input to gate cortical throughput in the nucleus accumbens. NA neurons exhibit a bistable membrane potential, characterized by a very negative resting membrane potential (down state), periodically interrupted by plateau depolarizations (up state), during which the cells may fire in response to cortical inputs. A dynamic ensemble can be the result of a distributed set of neurons in their up state, determined by the moment‐to‐moment changes in the spatial distribution of hippocampal inputs responsible for transitions to the up state. Ensembles may change as an adaptation to the contextual information provided by the hippocampal input. Furthermore, for dynamic ensembles to be functionally relevant, the model calls for near synchronous transitions to the up state in a group of neurons. This can be accomplished by the cell‐to‐cell transfer of information via gap junctions, a mechanism that can allow for a transfer of slow electrical signals, including “up” events between coupled cells. Furthermore, gap junction permeability is tightly modulated by a number of factors, including levels of dopamine and nitric oxide, and cortical inputs, allowing for fine‐tuning of this synchronization of up events. The continuous selection of such dynamic ensembles in the NA may be disputed in schizophrenia, resulting in an inappropriate level of activity of thalamocortical systems.

Tonic D2-mediated attenuation of cortical excitation in nucleus accumbens neurons recorded in vitro

The effects of dopamine D1 and D2 selective drugs on the responses evoked in accumbens neurons by stimulation of cortical afferents were studied in an in vitro brain slice preparation. The D2-specific antagonist sulpiride (1-10 microM) increased, whereas the D2 agonist quinpirole (1-20 microM) occasionally attenuated the amplitude of stimulation-evoked EPSPs recorded in accumbens neurons. Administration of the D1 agonist SKF 38393 (3-10 microM) or the D1 antagonist SCH 23390 (10 microM) did not alter the EPSP amplitude, although an apparent change in the time course of the EPSP was often observed. In slices obtained from dopamine (DA)-depleted animals, sulpiride failed to induce changes in the amplitude of the EPSPs, whereas quinpirole produced a highly significant suppression of EPSP amplitude that was only occasionally observed in control slices. These results indicate that DA modulates the response of accumbens neurons to cortico-accumbens fiber stimulation via D2 receptors. Furthermore, these D2 receptors appear to be located presynaptically on the cortical afferent terminals, since this action of DA was not accompanied by changes in membrane potential, input resistance, or time constant, and was not modified by changes in the membrane potential. These data provide evidence for a tonic basal level of D2 receptor stimulation in the accumbens slice preparation.

Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex

The orbitofrontal cortex has been hypothesized to carry information regarding the value of expected rewards. Such information is essential for associative learning, which relies on comparisons between expected and obtained reward for generating instructive error signals. These error signals are thought to be conveyed by dopamine neurons. To test whether orbitofrontal cortex contributes to these error signals, we recorded from dopamine neurons in orbitofrontal-lesioned rats performing a reward learning task. Lesions caused marked changes in dopaminergic error signaling. However, the effect of lesions was not consistent with a simple loss of information regarding expected value. Instead, without orbitofrontal input, dopaminergic error signals failed to reflect internal information about the impending response that distinguished externally similar states leading to differently valued future rewards. These results are consistent with current conceptualizations of orbitofrontal cortex as supporting model-based behavior and suggest an unexpected role for this information in dopaminergic error signaling.

Interconnected Parallel Circuits between Rat Nucleus Accumbens and Thalamus Revealed by Retrograde Transynaptic Transport of Pseudorabies Virus

One of the primary outputs of the nucleus accumbens is directed to the mediodorsal thalamic nucleus (MD) via its projections to the ventral pallidum (VP), with the core andshell regions of the accumbens projecting to the lateral and medial aspects of the VP, respectively. In this study, the multisynaptic organization of nucleus accumbens projections was assessed using intracerebral injections of an attenuated strain of pseudorabies virus, a neurotropic α herpesvirus that replicates in synaptically linked neurons. Injection of pseudorabies virus into different regions of the MD or reticular thalamic nucleus (RTN) produced retrograde transynaptic infections that revealed multisynaptic interactions between these areas and the basal forebrain. Immunohistochemical localization of viral antigen at short postinoculation intervals confirmed that the medial MD (m-MD) receives direct projections from the medial VP, rostral RTN, and other regions previously shown to project to this region of the thalamus. At longer survival intervals, injections confined to the m-MD resulted in transynaptic infection of neurons in the accumbens shell but not in the core. Injections that also included the central segment of the MD produced retrograde infection of neurons in the lateral VP and the polymorph (pallidal) region of the olfactory tubercle (OT) and transynaptic infection of a small number of neurons in the rostral accumbens core. Injections in the lateral MD resulted in retrograde infection in the globus pallidus (GP) and in transynaptic infection in the caudate-putamen. Viral injections into the rostroventral pole of the RTN infected neurons in the medial and lateral VP and at longer postinoculation intervals, led to transynaptic infection of scattered neurons in the shell and core. Injection of virus into the intermediate RTN resulted in infection of medial VP neurons and second-order infection of neurons in the accumbens shell. Injections in the caudal RTN or the lateral MD resulted in direct retrograde labeling of cells within the GP and transynaptic infection of neurons in the caudate-putamen. These results indicate that the main output of VP neurons receiving inputs from the shell of the accumbens is heavily directed to the m-MD, whereas a small number of core neurons appear to influence the central MD via the lateral VP. Further segregation in the flow of information to the MD is apparent in the organization of VP and GP projections to subdivisions of the RTN that give rise to MD afferents. Collectively, these data provide a morphological basis for the control of the thalamocortical system by ventral striatal regions, in which parallel connections to the RTN may exert control over activity states of cortical regions.

Gamma and Delta Neural Oscillations and Association with Clinical Symptoms under Subanesthetic Ketamine

Several electrical neural oscillatory abnormalities have been associated with schizophrenia, although the underlying mechanisms of these oscillatory problems are unclear. Animal studies suggest that one of the key mechanisms of neural oscillations is through glutamatergic regulation; therefore, neural oscillations may provide a valuable animal–clinical interface on studying glutamatergic dysfunction in schizophrenia. To identify glutamatergic control of neural oscillation relevant to human subjects, we studied the effects of ketamine, an N-methyl-D-aspartate antagonist that can mimic some clinical aspects of schizophrenia, on auditory-evoked neural oscillations using a paired-click paradigm. This was a double-blind, placebo-controlled, crossover study of ketamine vs saline infusion on 10 healthy subjects. Clinically, infusion of ketamine in subanesthetic dose significantly increased thought disorder, withdrawal–retardation, and dissociative symptoms. Ketamine significantly augmented high-frequency oscillations (gamma band at 40–85 Hz, p=0.006) and reduced low-frequency oscillations (delta band at 1–5 Hz, p<0.001) compared with placebo. Importantly, the combined effect of increased gamma and reduced delta frequency oscillations was significantly associated with more withdrawal–retardation symptoms experienced during ketamine administration (p=0.02). Ketamine also reduced gating of the theta-alpha (5–12 Hz) range oscillation, an effect that mimics previously described deficits in schizophrenia patients and their first-degree relatives. In conclusion, acute ketamine appeared to mimic some aspects of neural oscillatory deficits in schizophrenia, and showed an opposite effect on scalp-recorded gamma vs low-frequency oscillations. These electrical oscillatory indexes of subanesthetic ketamine can be potentially used to cross-examine glutamatergic pharmacological effects in translational animal and human studies.

NMDA/AMPA Ratio Impacts State Transitions and Entrainment to Oscillations in a Computational Model of the Nucleus Accumbens Medium Spiny Projection Neuron

We describe a computational model of the principal cell in the nucleus accumbens (NAcb), the medium spiny projection (MSP) neuron. The model neuron, constructed in NEURON, includes all of the known ionic currents in these cells and receives synaptic input from simulated spike trains via NMDA, AMPA, and GABAA receptors. After tuning the model by adjusting maximal current conductances in each compartment, the model cell closely matched whole-cell recordings from an adult rat NAcb slice preparation. Synaptic inputs in the range of 1000-1300 Hz are required to maintain an “up” state in the model. Cell firing in the model required concurrent depolarization of several dendritic branches, which responded independently to afferent input. Depolarization from action potentials traveled to the tips of the dendritic branches and increased Ca2+ influx through voltage-gated Ca2+ channels. As NMDA/AMPA current ratios were increased, the membrane showed an increase in hysteresis of “up” and “down” state dwell times, but intrinsic bistability was not observed. The number of oscillatory inputs required to entrain the model cell was determined to be ∼20% of the “up” state inputs. Altering the NMDA/AMPA ratio had a profound effect on processing of afferent input, including the ability to entrain to oscillations in afferent input in the theta range (4-12 Hz). These results suggest that afferent information integration by the NAcb MSP cell may be compromised by pathology in which the NMDA current is altered or modulated, as has been proposed in both schizophrenia and addiction.

A Neonatal Ventral Hippocampal Lesion Causes Functional Deficits in Adult Prefrontal Cortical Interneurons

Animals with a neonatal ventral hippocampal lesion (NVHL) develop abnormal behaviors during or after adolescence, suggesting that early insults can have delayed consequences. Many of these behaviors depend on the prefrontal cortex (PFC), and we have reported that PFC pyramidal neurons of adult rats with an NVHL respond to stimulation of the ventral tegmental area with an increase in firing instead of the characteristic decrease. As the dopamine modulation of cortical interneurons matures during adolescence, these findings raise the possibility that maturation of local inhibitory circuits within the PFC may have been altered in NVHL rats. Here, we assessed the state of PFC interneurons in NVHL rats with in situ hybridization measures of the mRNAs for the calcium binding protein parvalbumin (PV) and the GABA synthesizing enzyme GAD67, as well as with electrophysiological measures of interneuron function. Although no differences were observed with PV or GAD67, whole-cell recordings in slices revealed abnormal responses to the D2 agonist quinpirole in interneurons from NVHL rats. The loss of D2 modulation of local inhibition in slices from NVHL rats was also evident in the absence of a lasting component in the D2 attenuation of excitatory synaptic responses in pyramidal neurons, which in sham treated rats was picrotoxin sensitive. The results suggest that the neonatal lesion causes improper maturation, but not loss, of PFC interneurons during adolescence, a finding consistent with current interpretations of imaging data in schizophrenia that suggest a hyperactive, “noisy” cortex underlying dysfunction in the PFC and other cortical areas.