CiteULike: Author Floresco

Dopaminergic regulation of limbic-striatal interplay.

SB Floresco — 2008-07-20T08:14:13-00:00

Journal of psychiatry & neuroscience : JPN, Vol. 32, No. 6. (November 2007), pp. 400-411.

Neurochemical, electrophysiological and behavioural evidence indicates that certain forms of goal-directed behaviours are mediated by complex and reciprocal interactions between limbic and dopamine (DA) inputs in the nucleus accumbens (NAc). Mesoaccumbens DA transmission appears to be compartmentalized; synaptic DA transmission is mediated by phasic burst firing of DA neurons, whereas extrasynaptic tonic DA levels are regulated by DA neuron population activity and limbic glutamatergic inputs to the NAc. DA release facilitated by limbic inputs and acting on D1 receptors can either potentiate or suppress neural activity driven by separate limbic inputs converging on the same postsynaptic NAc neurons. In turn, D1 receptors in the NAc mediate accuracy of search behaviour regulated by hippocampal-ventral striatal circuitries; D2 receptors appear to mediate motivational aspects of task performance. These findings suggest that dopaminergic modulation of limbic afferents to the NAc may be a cellular mechanism for input selection that governs the smooth coordination of behaviour by permitting information processed by one limbic region to temporarily exert control over the type and intensity of adaptive behavioural responses.

Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting.

AE Block — 2008-03-27T23:00:43-00:00

Cereb Cortex, Vol. 17, No. 7. (July 2007), pp. 1625-1636.

The mediodorsal nuclei of thalamus (MD), prefrontal cortex (PFC), and nucleus accumbens core (NAc) form an interconnected network that may work together to subserve certain forms of behavioral flexibility. The present study investigated the functional interactions between these regions during performance of a cross-maze-based strategy set-shifting task. In Experiment 1, reversible bilateral inactivation of the MD via infusions of bupivacaine did not impair simple discrimination learning, but did disrupt shifting from response to visual cue discrimination strategy, and vice versa. This impairment was due to an increase in perseverative errors. In Experiment 2, asymmetrical disconnection inactivations of the MD on one side of the brain and PFC on the other also caused a perseverative deficit when rats were required to shift from a response to a visual cue discrimination strategy, as did disconnections between the PFC and the NAc. However, inactivation of the MD on one side of the brain and the NAc contralaterally resulted in a selective increase in never-reinforced errors, suggesting this pathway is important for eliminating inappropriate strategies during set shifting. These data indicate that set shifting is mediated by a distributed neural circuit, with separate neural pathways contributing dissociable components to this type of behavioral flexibility.

Dopaminergic regulation of inhibitory and excitatory transmission in the basolateral amygdala-prefrontal cortical pathway.

SB Floresco — 2007-11-15T16:01:13-00:00

J Neurosci, Vol. 27, No. 8. (21 February 2007), pp. 2045-2057.

Projections from the basolateral amygdala (BLA) and dopamine (DA) input from the ventral tegmental area (VTA) converge in the medial prefrontal cortex (mPFC), forming a neural circuit implicated in certain cognitive and emotional processes. However, the role that DA plays in modulating activity in the BLA-mPFC pathway is unknown. The present study investigated the mechanisms by which DA modulates BLA-evoked changes in mPFC neural activity, using extracellular single-unit recordings in urethane-anesthetized rats. BLA stimulation evoked two distinct types of responses in separate populations of mPFC neurons: monosynaptic, excitatory responses and, more commonly, inhibition of spontaneous firing. Stimulation of the VTA or local iontophoretic application of DA attenuated BLA-evoked inhibition of PFC neuron firing. Administration of selective DA receptor agonists revealed that these effects were mediated by D2 and D4 (but not D1) receptors. In addition, VTA stimulation or DA application attenuated BLA-evoked firing of a separate population of mPFC neurons in a frequency-dependent manner; firing evoked by higher-frequency stimulation of the BLA was less inhibited than that evoked by single-pulse stimulation. Attenuation of BLA-evoked firing was also induced by of D1 (but not D2 or D4) receptor agonists. These data indicate that dissociable DA receptor mechanisms regulate the balance of excitatory and inhibitory transmission in BLA-mPFC circuits, biasing toward an increase in the excitatory influence that the BLA exerts over populations of mPFC neurons. These findings may have important implications for understanding the pathophysiology underlying emotional and cognitive disturbances present in disorders such as depression and drug addiction.

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

Anthony Grace — 2007-04-04T14:05:09-00:00

Trends in Neurosciences, Vol. In Press, Corrected Proof

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.

Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission

Stan Floresco — 2006-12-07T09:27:27-00:00

Nat Neurosci, Vol. 6, No. 9. (2003), pp. 968-973.

Magnitude of Dopamine Release in Medial Prefrontal Cortex Predicts Accuracy of Memory on a Delayed Response Task

Anthony Phillips — 2007-01-16T15:50:29-00:00

J. Neurosci., Vol. 24, No. 2. (14 January 2004), pp. 547-553.

Modulation of neural function in the prefrontal cortex (PFC) by dopamine (DA) is essential for higher cognitive processes related to attention, working memory, and planning of future behavior. The present study demonstrates that DA efflux in the PFC is increased in a phasic manner when a rat engages in search behavior for food reward on an eight arm radial maze guided by memory, independent of whether or not reward is obtained for making the correct choice. Furthermore, disruption of accurate recall of the correct pattern of arms induced by increasing the delay period from 30 min to 1 or 6 hr, is associated with attenuated DA efflux during the retrieval phase of the task. The observed increase in DA efflux in the absence of reward at a 30 min delay and the minimal increase during consumption of the same quantity of food during poor performance after an unexpected 6 hr delay, argue against a simple relationship between DA function in the PFC and reward processes. Instead, these data demonstrate a close functional relationship between the release of DA from terminals within the PFC and the retrieval of specific trial unique memories; furthermore, the magnitude of mesocortical DA efflux is predictive of the accuracy of this form of memory. 10.1523/JNEUROSCI.4653-03.2004

Gating of hippocampal-evoked activity in prefrontal cortical neurons by inputs from the mediodorsal thalamus and ventral tegmental area.

SB Floresco — 2006-12-04T12:39:46-00:00

J Neurosci, Vol. 23, No. 9. (1 May 2003), pp. 3930-3943.

Projections from the hippocampus, the mediodorsal thalamus (MD), and the ventral tegmental area (VTA) form interconnected neural circuits that converge in the prefrontal cortex (PFC) to participate in the regulation of executive functions. The present study assessed the roles that the MD and VTA play in regulating the hippocampal-PFC pathway using extracellular single-unit recordings in urethane-anesthetized rats. MD stimulation inhibited PFC neuron firing (approximately 100 msec duration) evoked by fimbria/fornix (FF) stimulation in a majority of neurons tested. However, this effect was reduced if activation of thalamocortical inputs occurred almost simultaneously (10 msec) with stimulation of the FF. In a separate population of neurons, burst stimulation of the MD produced a short-term (approximately 100 msec) inhibition or facilitation of FF-evoked firing in 66 and 33% of PFC neurons, respectively. Moreover, tetanic stimulation of the MD caused a longer-lasting (approximately 5 min) potentiation of FF-evoked firing. Burst stimulation of the VTA inhibited FF-evoked firing in a frequency-dependent manner: firing evoked by higher-frequency trains of pulses to the FF was less inhibited than firing evoked by single-pulse stimulation. The inhibitory actions of VTA stimulation were augmented by D1 receptor antagonism and attenuated by D2 and D4 antagonists. Moreover, stimulation of the MD 10 msec before stimulation of the FF attenuated the VTA-mediated inhibition of evoked firing. Thus, both the MD and VTA exert a complex gating action over PFC neural activity, either facilitating or inhibiting firing in the hippocampal-PFC pathway depending on the frequency and relative timing of the arrival of afferent input.

Mesocortical dopamine modulation of executive functions: beyond working memory.

SB Floresco — 2006-12-04T12:36:22-00:00

Psychopharmacology (Berl), Vol. 188, No. 4. (November 2006), pp. 567-585.

RATIONALE: Dopamine (DA) neurotransmission in the prefrontal cortex (PFC) is known to play an essential role in mediating executive functions such as the working memory. DA exerts these effects by acting on D(1) receptors because blockade or stimulation of these receptors in the PFC can impair performance on delayed response tasks. However, comparatively less is known about dopaminergic mechanisms that mediate other executive functions regulated by the PFC. Furthermore, the functional importance of other DA receptor subtypes that reside on PFC neurons (D(2) and D(4)) is unclear. OBJECTIVES: This review will summarize previous findings and previously unpublished data addressing the contribution of PFC DA to higher-order cognition. We will compare the DA receptor mechanisms, which regulate executive functions such as working memory, behavioral flexibility, and decision-making. RESULTS AND CONCLUSIONS: Whereas PFC D(1) receptor activity is of primary importance in working memory, D(1) and D(2) receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the "inverted U-shaped" function of D(1) receptor activity mediating working memory does not necessarily apply to other PFC functions. DA in different subregions of the PFC also mediates decision-making assessed with delay discounting or effort-based procedures, and we report that D(1), D(2), and D(4) receptors in the medial PFC contribute to decision-making when animals must bias the direction of behavior to avoid aversive stimuli, assessed with a conditioned punishment procedure. Thus, mesocortical DA modulation of distinct executive functions is subserved by dissociable profiles of DA receptor activity in the PFC.

Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons.

SB Floresco — 2006-12-04T12:30:29-00:00

J Neurosci, Vol. 21, No. 13. (1 July 2001), pp. 4915-4922.

Several studies have shown that the mesolimbic dopamine (DA) system is strongly influenced by the ventral subiculum (vSub) of the hippocampus. To examine whether this occurs by activation of DA neuron firing, the effects of chemical stimulation of the vSub on ventral tegmental area (VTA) DA neuron activity were examined using extracellular single-unit recordings. Infusions of NMDA into the vSub increased the number of spontaneously firing DA cells recorded per electrode track, while having no effect on firing rate or burst firing. This response was abolished by intranucleus accumbens (NAc) infusions of the glutamate receptor antagonist kynurenic acid. This effect did not involve the prefrontal cortex, because infusions of tetrodotoxin into the prefrontal cortex did not affect the increase in spontaneously active DA cells. Infusions of either kynurenic acid into the NAc or tetrodotoxin into the vSub decreased the firing rate and burst firing of DA neurons without altering the number of spontaneously active DA neurons. These data show that glutamatergic afferents from the vSub to the NAc exert a potent excitatory effect on VTA DA neurons, influencing both DA neuron population activity and the regulation of the firing properties of these neurons. As a result, dysfunctions in hippocampal circuitries may contribute to the hyperexcitable state of the DA system that is present in schizophrenia.

Multiple Dopamine Receptor Subtypes in the Medial Prefrontal Cortex of the Rat Regulate Set-Shifting

Stan Floresco — 2005-07-13T16:17:15-00:00

Neuropsychopharmacology, Vol. aop, No. current. (13 July 2005)

Developing predictive animal models and establishing a preclinical trials network for assessing treatment effects on cognition in schizophrenia.

SB Floresco — 2005-11-04T21:34:33-00:00

Schizophr Bull, Vol. 31, No. 4. (October 2005), pp. 888-894.

Animal models are an essential initial phase in the discovery of novel drugs to treat psychiatric disorders. At the sixth Measurement and Treatment Research to Improve Cognition in Schizophrenia conference, "New Approaches to Assessing and Improving Cognition in Schizophrenia," a discussion group was formed to address issues related to the development of predictive animal models of cognition that may be used as preclinical assays for putative cognitive enhancers. We identified 2 complementary approaches used to model cognitive impairments in animals. First, basic lesion/pharmacological models provide information about the particular neural substrates that may underlie different types of cognitive deficits found in schizophrenia. Findings from these studies can be mapped onto the second, more elaborate and etiologically relevant neurodevelopmental models of the disorder to ascertain which cognitive systems may be altered by early developmental insults. Particular attention must be given to the types of animal tasks used, in order to relate directly to the cognitive domains that are affected in schizophrenia patients. Importantly, the validation and standardization of the methodologies used in these preclinical assays would require the establishment of a preclinical trials network, serving as a counterpart to the recently established Treatment Units for Research on Neurocognition and Schizophrenia. The need to validate specific approaches to assess cognitive functions relevant to schizophrenia could be satisfied by a concerted effort enabled by a new funding directive from the National Institute of Mental Health with the explicit purpose of facilitating research on these models and assessing novel drug therapies that may be used to ameliorate the cognitive deficits in schizophrenia.