Nandakumar S. Narayanan

Top-Down Control of Motor Cortex Ensembles by Dorsomedial Prefrontal Cortex

Dorsomedial prefrontal cortex is critical for the temporal control of behavior. Dorsomedial prefrontal cortex might alter neuronal activity in areas such as motor cortex to inhibit temporally inappropriate responses. We tested this hypothesis by recording from neuronal ensembles in rodent dorsomedial prefrontal cortex during a delayed-response task. One-third of dorsomedial prefrontal neurons were significantly modulated during the delay period. The activity of many of these neurons was predictive of premature responding. We then reversibly inactivated dorsomedial prefrontal cortex while recording ensemble activity in motor cortex. Inactivation of dorsomedial prefrontal cortex reduced delay-related firing, but not response-related firing, in motor cortex. Finally, we made simultaneous recordings in dorsomedial prefrontal cortex and motor cortex and found strong delay-related temporal correlations between neurons in the two cortical areas. These data suggest that functional interactions between dorsomedial prefrontal cortex and motor cortex might serve as a top-down control signal that inhibits inappropriate responding.

The Role of the Prefrontal Cortex in the Maintenance of Verbal Working Memory: An Event-Related fMRI Analysis.

Neuroimaging studies have been inconclusive in characterizing the role of the prefrontal cortex (PFC) for maintaining increasingly larger amounts of information in working memory (WM). To address this question, the authors collected event-related functional MRI data while participants performed an item-recognition task in which the number of to-be-remembered letters was parametrically modulated. During maintenance of information in WM, the dorsolateral and the ventrolateral PFC exhibited linearly increasing activation in response to increasing WM load. Prefrontal regions could not be distinguished from one another on the basis of load sensitivity, but the dorsolateral PFC had stronger functional connectivity with the parietal and motor cortex than the ventrolateral PFC. These results suggest an increasingly important role for the PFC in actively maintaining information as the amount of that information increases.

Imaging the spread of reversible brain inactivations using fluorescent muscimol

Muscimol is a GABA A-agonist that causes rapid and reversible suppression of neurophysiological activity. Interpretations of the effects of muscimol infusions into the brain have been limited because of uncertainty about spread of the drug around the injection site. To solve this problem, the present study explored the use of a fluorophore-conjugated muscimol molecule (FCM). Whole-cell recordings from horizontal brain slices demonstrated that bath-applied FCM acts like muscimol in reversibly suppressing excitatory synaptic transmission. Two types of in vivo experiments demonstrated that the behavioral effects of FCM infusion are similar to the behavioral effects of muscimol infusion. FCM infusion into the rat amygdala before fear conditioning impaired both cued and contextual freezing, which were tested 24 or 48 h later. Normal fear conditioning occurred when these same rats were subsequently given phosphate-buffered saline infusions. FCM infusion into the dorsomedial prefrontal cortex impaired accuracy during a delayed-response task. Histological analysis showed that the region of fluorescence was restricted to 0.5-1mm from the injection site. Myelinated fiber tracts acted as diffusional barriers, thereby shaping the overall spread of fluorescence. The results suggest that FCM is indeed useful for exploring the function of small brain regions.

Common medial frontal mechanisms of adaptive control in humans and rodents

In this report we describe how common brain networks within the medial frontal cortex (MFC) facilitate adaptive behavioral control in rodents and humans. We demonstrate that after errors, low-frequency oscillations below 12 Hz are modulated over the midfrontal cortex in humans and within the prelimbic and anterior cingulate regions of the MFC in rats. These oscillations were phase locked between the MFC and motor areas in both rats and humans. In rats, single neurons that encoded prior behavioral outcomes were phase coherent with low-frequency field oscillations, particularly after errors. Inactivating the medial frontal regions in rats led to impaired behavioral adjustments after errors, eliminated the differential expression of low-frequency oscillations after errors and increased low-frequency spike-field coupling within the motor cortex. Our results describe a new mechanism for behavioral adaptation through low-frequency oscillations and elucidate how medial frontal networks synchronize brain activity to guide performance.

Metabolic hormones, dopamine circuits, and feeding

Recent evidence has emerged demonstrating that metabolic hormones such as ghrelin and leptin can act on ventral tegmental area (VTA) midbrain dopamine neurons to influence feeding. The VTA is the origin of mesolimbic dopamine neurons that project to the nucleus accumbens (NAc) to influence behavior. While blockade of dopamine via systemic antagonists or targeted gene delete can impair food intake, local NAc dopamine manipulations have little effect on food intake. Notably, non-dopaminergic manipulations in the VTA and NAc produce more consistent effects on feeding and food choice. More recent genetic evidence supports a role for the substantia nigra-striatal dopamine pathways in food intake, while the VTA-NAc circuit is more likely involved in higher-order aspects of food acquisition, such as motivation and cue associations. This rich and complex literature should be considered in models of how peripheral hormones influence feeding behavior via action on the midbrain circuits.

Redundancy and Synergy of Neuronal Ensembles in Motor Cortex

We examined the ability of neuronal ensembles from rat motor cortex to predict behavioral performance during a reaction time task. We found that neurons that were the best individual predictors of task performance were not necessarily the neurons that contributed the most predictive information to an ensemble of neurons. To understand this result, we applied a framework for quantifying statistical relationships between neurons (Schneidman et al., 2003) to all possible combinations of neurons within our ensembles. We found that almost all neurons (96%) contributed redundant predictive information to the ensembles. This redundancy resulted in the maintenance of predictive information despite the removal of many neurons from each ensemble. Moreover, the balance of synergistic and redundant interactions depended on the number of neurons in the ensemble. Small ensembles could exhibit synergistic interactions (e.g., 23 ± 9% of ensembles with two neurons were synergistic). In contrast, larger ensembles exhibited mostly redundant interactions (e.g., 99 ± 0.1% of ensembles with eight neurons were redundant). We discuss these results with regard to constraints on interpreting neuronal ensemble data and with respect to motor cortex involvement in reaction time performance.

Medial prefrontal D1 dopamine neurons control food intake

Although the prefrontal cortex influences motivated behavior, its role in food intake remains unclear. Here, we demonstrate a role for D1-type dopamine receptor–expressing neurons in the medial prefrontal cortex (mPFC) in the regulation of feeding. Food intake increases activity in D1 neurons of the mPFC in mice, and optogenetic photostimulation of D1 neurons increases feeding. Conversely, inhibition of D1 neurons decreases intake. Stimulation-based mapping of prefrontal D1 neuron projections implicates the medial basolateral amygdala (mBLA) as a downstream target of these afferents. mBLA neurons activated by prefrontal D1 stimulation are CaMKII positive and closely juxtaposed to prefrontal D1 axon terminals. Finally, photostimulating these axons in the mBLA is sufficient to increase feeding, recapitulating the effects of mPFC D1 stimulation. These data describe a new circuit for top-down control of food intake.

Delay Activity in Rodent Frontal Cortex During a Simple Reaction Time Task

To understand how different parts of the frontal cortex control the timing of action, we characterized the firing patterns of single neurons in two areas of rodent frontal cortex-dorsomedial prefrontal cortex (dmPFC) and motor cortex-during a simple reaction time task. Principal component analysis was used to identify major patterns of delay-related activity in frontal cortex: ramping activity and sustained delay activity. These patterns were similar in dmPFC and motor cortex and did not change as animals learned to respond at novel delays. Many neurons in both areas were modulated early in the delay period. Other neurons were modulated in a persistent manner over the duration of the delay period. Delay-related modulations started earlier in motor cortex than in dmPFC and terminated around different task events (at the time of release in dmPFC, just before release of the lever in motor cortex). A subpopulation of neurons was found in dmPFC, but not motor cortex, that fired in response to the trigger stimulus. These results suggest that populations of neurons in rodent frontal cortex are coordinated during delay periods to enable proactive inhibitory control of action.

Neuronal Correlates of Post-Error Slowing in the Rat Dorsomedial Prefrontal Cortex

Rats with impaired function in dorsomedial regions of the prefrontal cortex (dmPFC) are unable to maintain a behavioral response over a delay period. Here we report that neurons in this cortical region are prominently modulated after errors in a tone-cued, simple reaction time task and that inactivation of dmPFC attenuates a slowing of reaction times that is observed following errors. Using methods for chronic single-unit recording, we found that approximately one-third of dmPFC neurons were modulated after errors, and 28% of these neurons had increased posterror firing that persisted into the delay period of the following trial. In contrast to dmPFC, no such neurons were found in motor cortex. Our results implicate the dorsomedial prefrontal cortex in a form of retrospective working memory that improves task performance following errors.

Prefrontal dopamine signaling and cognitive symptoms of Parkinson's disease.

Abstract Cognitive dysfunction is a common symptom of Parkinson’s disease (PD) that causes significant morbidity and mortality. The severity of these symptoms ranges from minor executive symptoms to frank dementia involving multiple domains. In the present review, we will concentrate on the aspects of cognitive impairment associated with prefrontal dopaminergic dysfunction, seen in non-demented patients with PD. These symptoms include executive dysfunction and disorders of thought, such as hallucinations and psychosis. Such symptoms may go on to predict dementia related to PD, which involves amnestic dysfunction and is typically seen later in the disease. Cognitive symptoms are associated with dysfunction in cholinergic circuits, in addition to the abnormalities in the prefrontal dopaminergic system. These circuits can be carefully studied and evaluated in PD, and could be leveraged to treat difficult clinical problems related to cognitive symptoms of PD.