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. This finding raised the question as to whether the midline thalamus is an important hub in frontotemporal circuitry, and by extension, to what extent is it a critical contributor to executive function? To get a better understanding of the organization of the prefrontal-thalamic-hippocampal interconnections, we first traced the connections of different midline thalamic nuclei. This work identified a topographical arrangement of cortical connections of the dorsal and ventral midline thalamic structures suggesting that the so-called non-specific midline thalamus is very specific in how it interacts with different cortical regions. Second, we identified, for the first time, a disynaptic input from the anterior portion of the dorsal hippocampus to the dorsal and ventral regions of the prefrontal cortex. Here we discovered three interconnected parallel circuits between the dorsal hippocampus and prefrontal cortex with connecting links in the ventral hippocampus, the lateral septum, and midline thalamus. We were particularly attentive to sex differences as we found that septal lesions caused major disturbances in the neural organization and arborization of prefrontal and hippocampal structures, which differed substantially between male and female rats. There were also differences in the way these animals responded defensively when subjected to anxiety provoking situations. Moreover, the sexual dimorphic behavioral changes in anxiety were accompanied by differences in the quality and quantity of ultrasonic vocalizations providing the first evidence to date that prefrontal-septal-hippocampal interconnections differentially influence the expression of anxiety in males and females. In the coming years, we will investigate more closely the interaction between the septum, hippocampus and prefrontal cortex, as well as their neuromodulation by acetylcholine, in certain types of decision-making behavior. 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 decisions served by different septal 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. If, however, we acutely activate the alpha-2a-receptors during a stressful episode, the option to choose risky behaviors is substantially increased. In the coming year we will further explore 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 (Messanvi et al., Psychopharm, 2020). In the past year, we have targeted galanin receptor 1 specific cells in the hippocampus and prefrontal cortex using cell-type specific inactivation. For this, we have 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, and other related structures such as the nucleus accumbens and amygdala, 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. The next step is to confirm the contribution of the specific pathway from the brainstem to the prefrontal and hippocampal areas to impulse control and establish the molecular signature of these interacting regions through calcium signaling. 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.