Neural Circuits Underlying the Control of Executive and Emotional Behavior

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

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, neuropharmacology, optogenetic stimulation, fiber photometry 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. The identification of the septum as an anatomical link between the dorsal hippocampus and prefrontal cortex prompted us to further explore the organization of the connections of these structures. Septal damage is associated with various mental disorders due to its impact on the limbic system which plays a critical role in regulating emotions, behavior and cognition. In addition, the progressive deterioration of the septal and extra-septal cholinergic neurons in the basal forebrain in degenerative disorders like Alzheimer’s disease and in normal aging further implicates this structure in cognition and memory. We are currently investigating the intrinsic circuitry of the hippocampus and septal complex, with an eye toward genetically defined cell types. We have started on this with transcriptomics, in an attempt to understand the molecular signature of neurons with different local connections, projection targets, and receptors profiles. This aligns with our objective of tracking gene expression profiles during behavioral changes in early life development. 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. In the past year, we made two 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 anxiety-inducing stress, caused by GABAA inverse agonists promotes a very conservative and safe decision-making strategy. That is, they become risk averse. If, however, we acutely activate the alpha-2a-receptors while stressed, the decisions begin to shift more towards risk. In addition, the decision-making is faster, and reward collection is faster even when the risky decision led to an overall reward loss. We found that these changes in decision-making behavior correlated with norepinephrine (NE) release in the basolateral amygdala (BLA), a brain structure intimately connected with the hippocampus and prefrontal cortex. While stress increased BLA-NE release and potentially risk-taking behavior, antagonizing the alpha-2a-receptors showed the opposite effect by reducing NE release. We are currently exploring this mechanism by combining receptor specific pharmacology and fiber photometric 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 the neuropeptide galanin which is 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 (GalR1) mediated neurotransmission in these areas modulate selective attention and impulse control mechanisms. In the past year, we explored this mechanism further and showed that: a) GalR1 is predominantly expressed in glutamatergic neurons with the highest expressions the ventral prefrontal cortex and ventral hippocampus, b) ventral prefrontal and ventral hippocampal GalR1-expressing neurons project widely to brain areas involved in attention and impulse control including the septum, ventral striatum and midline thalamus, and c) ventral hippocampal GalR1 fibers densely target neurons in the deep layers of the ventral prefrontal cortex, highlighting the important finding that galanin within the frontotemporal circuitry can fine-tune aspects of cognitive-executive behavior. More specifically, the genetic targeting of GalR1 expressing neurons in the ventral prefrontal and ventral hippocampus using optogenetic stimulation suggested that although the two brain regions contribute differentially, the ventral prefrontal cortex was a stronger driver of specific aspects of executive behavior. Optical stimulation of GALR1 neurons lowered target accuracy, increased trial omissions and, reduced impulsive responses, but only in the prefrontal cortex. Optogenetically exciting the GalR1-expressing neurons in the vHC had little impact on performance, which was surprising since lesioning both areas results in major attention and impulsive deficits. To reconcile this apparent difference, we established the cellular dynamics of these interacting structures through calcium signaling (i.e., fiber photometry) and discovered these two regions differentially signal aspects of behavior that enable controlled, inhibited, and accurate response selection; while prefrontal GalR1 neurons are directly involved in the control of attention, ventral hippocampal GalR1 neurons signal cognitive errors or negative events.. 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.