Biomedical subjects

Stan B Floresco

Publications and source records attributed to Stan B Floresco.

12 recordsLinked to original sources

PubMed2006

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

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.

Animals↗

PubMed2006

Alterations in behavioral flexibility by cannabinoid CB1 receptor agonists and antagonists.

RATIONALE: Cannabinoid CB1 receptors are expressed in the prefrontal cortex, but their role in mediating executive functions such as behavioral flexibility is unclear. OBJECTIVE: The present study examined the effect of pharmacological activation or blockade of the cannabinoid CB1 receptors on behavioral flexibility using a strategy set-shifting task conducted on a cross maze. MATERIALS AND METHODS: In experiment 1, rats initially were trained to turn left or right while ignoring the visual cue to obtain a food; on the second test day, rats had to inhibit the previously learned rule and approach the cue to obtain the food. In experiment 2, the order of discrimination training was reversed. RESULTS: Administration of the cannabinoid CB1 receptor agonist HU-210 before the set-shift on day 2 elicited dose-dependent effects on performance. A 20-microg/kg dose of HU-210 increased perseverative errors, whereas the effects of a lower, 5-microg/kg dose caused differential effects depending on whether rats were required to shift from a response to a visual-cue discrimination strategy or vice versa. Conversely, administration of a 2-mg/kg, but not a 5-mg/kg dose of the CB1 receptor antagonist AM251 reduced perseverative errors. CONCLUSIONS: These data demonstrate a biphasic and dose-sensitive role for the cannabinoid system in behavioral flexibility, which in turn may have clinical implications for the role of the endocannabinoid system in psychiatric disorders where behavioral flexibility is compromised.

Animals↗

PubMed2006

Systemic and local administration of estradiol into the prefrontal cortex or hippocampus differentially alters working memory.

The influence of estradiol on learning and memory is dependent on a number of factors. The effects of physiological levels of estradiol on the acquisition of a spatial working memory task mediated by the prefrontal cortex (PFC) and the hippocampus were examined in Experiment 1. Ovariectomized Long-Evans rats received daily injections of estradiol or vehicle were tested on the win-shift version of the radial arm maze. A high dose of estradiol benzoate (5 microg) enhanced acquisition of the task, whereas a low dose of estradiol (0.3 microg) increased the number of errors committed over 17 days of testing. Experiment 2 was conducted to examine site-specific influences of estradiol on spatial working memory in well-trained rats. Saline and estradiol cyclodextrin (0.1 and 0.9 microg) were infused into the prelimbic region of the PFC or dorsal hippocampus 40 min prior to testing on the win-shift task. Infusions of estradiol into both brain areas attenuated saline-infusion disruptions in working memory. Specifically, the higher dose of estradiol facilitated working memory when infused into the PFC, whereas the lower dose of estradiol facilitated performance when infused into the dorsal hippocampus. Moreover, working memory was significantly impaired 24 h after infusions of estradiol into the dorsal hippocampus but not the PFC. These data provide further evidence for the notion that estradiol can dose-dependently alter memory processes and suggest that facilitation or disruptions of working memory by estradiol are site- and time-specific.

Analysis of Variance↗

PubMed2006

Mesocortical dopamine modulation of executive functions: beyond working memory.

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 D1 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 (D2 and D4) 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 D1 receptor activity is of primary importance in working memory, D1 and D2 receptors act in a cooperative manner to facilitate behavioral flexibility. We note that the principle of the "inverted U-shaped" function of D1 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 D1, D2, and D4 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.

Animals↗

PubMed2006

Dissociable roles for the nucleus accumbens core and shell in regulating set shifting.

The ability to behave in a flexible manner is an executive function mediated in part by different regions of the prefrontal cortex. The present study investigated the role of two major efferents of the prefrontal cortex, the nucleus accumbens (NAc) core and shell, in behavioral flexibility using a maze-based strategy set-shifting task. During initial discrimination training, rats learned to use either an egocentric response or a visual-cue discrimination strategy to obtain food reward. During the set shift, animals had to shift from the previously acquired response or visual-cue-based strategy and learn the alternate discrimination. Inactivation of the NAc core, induced by infusion of the GABA agonists baclofen and muscimol, did not impair initial acquisition of either a response or visual-cue discrimination but severely disrupted shifting from one strategy to another. Analysis of the type of errors revealed that impairments in set shifting were not attributable to increased perseveration but to a disruption of the acquisition and maintenance of a new strategy. In contrast, inactivation of the NAc shell did not impair acquisition of either a response or a visual-cue discrimination, or shifting from one strategy to another. However, inactivation of the NAc shell before initial discrimination training improved performance during the set shift relative to control animals. These data indicate that the NAc core and shell make dissociable contributions to behavioral flexibility during set shifting. The NAc core facilitates the acquisition and maintenance of novel behavioral strategies and elimination of inappropriate response options, whereas the shell may mediate learning about irrelevant stimuli.

Analysis of Variance↗

PubMed2006

Amygdala-prefrontal cortical circuitry regulates effort-based decision making.

The basolateral amygdala (BLA) and the anterior cingulate cortex (ACC) region of the prefrontal cortex form an interconnected neural circuit that may mediate certain types of decision-making processes. The present study assessed the role of this pathway in effort-based decision making using a cost-benefit T-maze task. Rats were given a choice of obtaining a high reward by climbing a 30-cm barrier in 1 arm (4 pellets; high-reward [HR] arm) or a small reward in the other arm with no barrier (2 pellets; low-reward [LR] arm). In Experiment 1, bilateral inactivation of the BLA via infusion of bupivacaine impaired decision making, reducing the preference for the HR arm. This effect was not due to spatial or motor deficits because BLA inactivation did not alter behavior when the amount of effort required to obtain either reward was equalized by placing a 2nd barrier in the LR arm. In Experiment 2, disconnection between the BLA and ACC, entailing a unilateral BLA inactivation combined with a contralateral ACC inactivation also impaired decision making. These data suggest that the serial transfer of information between the BLA and ACC guides response selection when evaluating the value of an expected outcome relative to the costs of performing a particular action.

Adaptation, Physiological↗

PubMed2006

Multiple dopamine receptor subtypes in the medial prefrontal cortex of the rat regulate set-shifting.

Dopamine (DA) input to the prefrontal cortex (PFC), acting on D1 receptors, plays an essential role in mediating working memory functions. In comparison, less is known about the importance of distinct PFC DA receptor subtypes in mediating executive functions such as set-shifting. The present study assessed the effects of microinfusion of D2 and D4 receptor antagonists, and D1, D2, and D4 receptor agonists into the PFC on performance of a maze-based set-shifting task. In Experiment 1, rats were trained on a response discrimination task, and then on a visual-cue discrimination task requiring rats to suppress the use of the response strategy and approach the previously irrelevant cue to locate food. In Experiment 2, the order of training was reversed. Infusions of the D2 antagonist eticlopride, or the D4 agonist PD-168,077, impaired shifting from a response to a visual-cue discrimination strategy and vice versa, and caused a selective increase in perseverative errors. In contrast, infusions of the D4 antagonist L-745,870 improved set-shifting. Infusions of the D1 agonist SKF81297 or the D2 agonist quinpirole caused no reliable effect. These data, in combination with previous reports of impaired set-shifting following D1 receptor blockade, suggest that multiple receptors in the PFC are essential for set-shifting and that the mechanisms by which PFC DA mediates behavioral flexibility may be different from those underlying working memory. These findings may have important implications for developing novel treatments for cognitive deficits observed in disorders such as attentional deficit and hyperactivity disorder and schizophrenia.

Analysis of Variance↗

PubMed2005

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

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.

Animals↗

PubMed2004

Magnitude of dopamine release in medial prefrontal cortex predicts accuracy of memory on a delayed response task.

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.

Animals↗

PubMed2003

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

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.

Action Potentials↗

PubMed2003

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

The mesolimbic dopamine system is centrally involved in reward and goal-directed behavior, and it has been implicated in multiple psychiatric disorders. Understanding the mechanism by which dopamine participates in these activities requires comprehension of the dynamics of dopamine release. Here we report dissociable regulation of dopamine neuron discharge by two separate afferent systems in rats; inhibition of pallidal afferents selectively increased the population activity of dopamine neurons, whereas activation of pedunculopontine inputs increased burst firing. Only the increase in population activity increased ventral striatal dopamine efflux. After blockade of dopamine reuptake, however, enhanced bursting increased dopamine efflux three times more than did enhanced population activity. These results provide insight into multiple regulatory systems that modulate dopamine system function: burst firing induces massive synaptic dopamine release, which is rapidly removed by reuptake before escaping the synaptic cleft, whereas increased population activity modulates tonic extrasynaptic dopamine levels that are less influenced by reuptake.

Afferent Pathways↗

PubMed2003

Electrophysiological interactions between striatal glutamatergic and dopaminergic systems.

Glutamatergic and dopaminergic systems play a primary role in frontal-subcortical circuits involved in motor and cognitive functions. Considerable evidence has emerged indicating that the complex interaction between these neurotransmitter systems within the dorsal striatum and nucleus accumbens is critically involved in the gating of information flow in these highly integrative brain regions. As a result, disruptions of the interaction between glutamate and dopamine has been proposed as a pathological basis for a number of disorders, including the pathophysiology of schizophrenia. In this chapter, we discuss recent studies that have significantly advanced our understanding of the reciprocal interactions between glutamatergic and dopaminergic systems within the striatal complex in the normal brain and in pathological states.

Animals↗