Neural Circuits Underlying the Control of Executive and Emotional Behavior

National Institute Of Mental Health

Investigators

Linked publications & trials

Abstract

Work in my lab and that of other investigators has revealed that so-called prefrontal function involves a broad network of areas including not only the prefrontal cortex but also the hippocampus, basal ganglia, and certain thalamic nuclei. These structures are anatomically connected in a particular way that is shared by rodents, humans, and non-human primates, suggesting a mammalian network underlying the forebrain control of behavior. Its relation to the regulation of neurotransmitters, such as dopamine, makes it central not only to understanding executive function, but also to schizophrenia and other disorders in humans. As this circuitry is central to our understanding of a wide range of human cognitive abilities and disorders, our future research will continue to investigate its underlying neurobiology, always retaining as its focal point the measurement and quantification of behavior. One major theme of our research focuses on the complex interplay of frontal and temporal lobe structures in cognition and emotion. Our previous and ongoing work has shown that frontotemporal circuitry is critical for adaptive behavioral control and emotion regulation. We have thus far focused on the role of long-range connections in this network, combining behavior, inactivation, neuropharmacology, and neuroanatomical tracing. A powerful method for understanding this large-scale circuitry of frontotemporal organization, has been the use of polysynaptic anatomical tracers to delineate circuits or pathways of connected neurons. A few years ago, we showed that different regions of the hippocampus receive input from different thalamic nuclei, which in turn receive input from different cortical structures. More recently, we investigated projections going in the opposite direction by establishing indirect inputs to different prefrontal cortical regions. Here, we took advantage of the fluorescent recombinants that have been developed and validated in the past years. We discovered parallel multisynaptic pathways through which the neurons in the CA3 region of the dorsal hippocampus provide indirect input to both dorsal and ventral regions of the prefrontal cortex via different relays. Thus, the dorsal CA3, which is best known for its role in spatial memory, has the potential to significantly shape prefrontal responses through a range of intermediary relays, including the septum, and ventral hippocampus. These findings reinforce and extend our growing perspective that temporal lobe structures directly and indirectly contribute strongly to the expression of prefrontal executive function. In the coming years, we will investigate more closely the real time neural activity of the dorsal CA3 region of the hippocampus during prefrontal dependent behaviors that require decision making, selective and spatial attention and response control and cognitive flexibility. Drawing from our toolbox of ablation, pharmacological blockade, and cell-type specific suppression or stimulation using genetically encoded agents, we will attempt to understand the specific types of behaviors served by the different hippocampal - prefrontal pathways. Recently, we discovered that some types of decisions, particularly those involving time, critically and specifically rely on an intact ventral hippocampus. For such decisions, the prefrontal cortex alone, appears to play a relatively minor role. At the same time, the hippocampus works together with the prefrontal cortex in other categories of decision, such as those requiring the inhibition of a prepotent response. Neurotransmitter and neuropeptide levels are known to selectively modulate the nature of this hippocampal contribution. For example, we were able to improve decision-making skills in control rats by pharmacologically stimulating the alpha-2a-receptors directly in the ventral hippocampus, whereas stimulating dopamine D1 receptors had no such effect. This modulation of cognitive decision-making may be related to the successful use of noradrenergic stimulants to relieve symptoms of attention deficit hyperactivity disorder, where the site of action is presumed to be in the prefrontal cortex but never the hippocampus. In the past year, we made two additional discoveries on the role of noradrenaline in cognitive function. First, we discovered an alpha 2-adrenergic mechanism in stress induced decision-making. Specifically, we found that stress, which is associated with significant increases in noradrenaline in the hippocampus, promotes safe decision-making. That is, they become risk averse. If, however, we acutely activate the alpha-2a-receptors during a stressful episode, the risk seeking behavior is substantially increased, a behavior that was reversed when those same receptors were antagonized. We are currently exploring this mechanism by combining receptor specific pharmacology and optogenetic methods to elucidate the specific pathway that potentially worsens or trigger risky behaviors observed in both clinical and non-clinical populations. Our second discovery focuses specifically on neuropeptides like galanin which are co-released with noradrenaline. Galanin receptors are highly expressed in the prefrontal cortex and the hippocampus. Thus, galanin released into these structures may participate in cognitive-control mechanisms that require hippocampal-prefrontal cortical circuitry. This hypothesis was supported by our recent discovery that Galanin receptor 1 mediated neurotransmission in these areas modulate impulse control mechanisms. In the past year, we explored this mechanism further. Using multiplex fluorescent in situ hybridization, we established that galanin receptor 1 is predominantly expressed in glutamatergic neurons with the highest expressions in the ventral prefrontal cortex (prelimbic and infralimbic regions) and the ventral hippocampus (CA1 pyramidal layer and the ventral subiculum). We then confirmed that ventral hippocampal galanin receptor 1 fibers were strongly targeting neurons in the prefrontal cortex, highlighting the important finding that galanin within the frontotemporal circuitry can fine-tune aspects of cognitive-executive behavior. More recently, we targeted galanin receptor 1 specific cells in the hippocampus and prefrontal cortex using cell-type specific inactivation. For this, we combined behavioral testing with optogenetic methods using a cre-dependent virus under the control of a galanin receptor 1 promotor. This reversible manipulation approach has allowed us to gauge the relative contributions of the hippocampus, prefrontal cortex to different types of cognitive decisions, with a high level of precision at both the behavioral and circuitry level. Our preliminary findings confirm that stimulation of galanin receptor 1 expressing cells modulate the degree of impulsivity in both prefrontal and hippocampus brain regions. We have also established the cellular dynamics of these interacting structures through calcium signaling (i.e., fiber photometry). Specifically, we have found that that cells in the CA1 region of the ventral hippocampus and cells in the ventral prefrontal cortex differentially signal aspects of behavior that enable controlled, inhibited, and accurate response selection. For example, cells in the ventral hippocampus are sensitive to reward loss and show heightened calcium signals following an omission or impulsive, premature responses. In contrast, cells in the prefrontal cortex are more sensitive to accurate detection of the stimuli and reward delivery. Understanding this interplay, as well as the effects of pharmacological agents in normalizing the contribution of these circuits, is a critical component of our research agenda that can have a direct clinical impact.