Haubensak Group Research
Circuit mechanics of emotions in the limbic system
Survival critically depends on recognizing what is important, and initiating appropriate behavioral responses - a process modulated by emotions. Fear, for instance, associates stimuli with threat and evokes defensive behaviors; emotions associated with reward induce the opposite. Emotions are a focal aspect of our mental selves, and linked to a variety of psychological conditions. But how are emotions wired in the brain? To investigate their underlying neural basis, we use molecular, pharmacogenetic, and optogenetic methods to map neural circuits for emotional behaviors in mice. Combining these manipulations with electrophysiological methods, we explore how these circuits control emotional states, and how genes and psychoactive drugs, in turn, modulate circuit activity, emotional states and behavior.
Understanding how various emotions emerge from the neurocircuitry of the brain and how these emotional states are modulated by genes and pharmacology is a complex problem. One straightforward approach is to investigate, in exemplary fashion, how basic emotions are processed in selected key elements of the brain emotion system. Numerous studies have established the limbic system as the central hub in emotion processing (LeDoux, 2000). It integrates sensory information, encodes emotional states, and instructs other brain centers to regulate physiology and behavior. However, it consists of many distinct and highly interconnected neuronal populations. Resolving how emotions are processed in this network at the level of single neural circuits is a major challenge. To address this problem, we combine genetic manipulation of brain circuitry to map circuit anatomy and function (Luo et al., 2008), using electrophysiological recordings (Du et al., 2009) for probing circuit interactions.
Circuit mechanisms of emotions
- Figure 1 (Click to view legend)
In a first foray, we are screening for local limbic microcircuits that could serve as key emotion hubs. Pharmacogenetics, optogenetics, and viral tracing disclosed a local inhibitory circuit of two antagonistic neuronal populations in the lateral central amygdala (CEl) that gates amygdala output to control conditioned fear (Haubensak et al., 2010). Results from combined pharmacogenetics and in vivo electrophysiological recordings suggest that antagonistic neuronal populations operate like a seesaw which alternates between two states: in the absence of a conditioned stimulus (CS), so called CEl-off neurons, identified by the expression of PKCδ (Figure 1A), are active, inhibiting their counterpart CEl-on neurons and amygdala output; in the presence of the CS, CEl-on neurons are active, inhibiting CEl-off neurons, which disinhibits amygdala output and fear signals to the brain stem (Figure 1B). In support of this model, initial pharmacogenetic experiments have shown that a reduction of CEl-off neuronal activity results in significantly higher amygdala output and conditioned freezing than usual. We are currently validating the proposed circuit mechanics with neural modeling (Figure 1C), optogenetic perturbations (Fig. 2A), electrophysiology and behavior. Using a similar strategy, we will screen for, and analyze, other local microcircuits in a similar manner to reveal general motifs in the neural circuit organization of emotion and brain function.
However, these microcircuits do not operate in isolation, but rather in cooperation with other brain structures. Cortical inputs, for instance, would make an excellent substrate for the top-down control of emotions by higher cognitive processes. Virus-based anatomical circuit tracing will identify this macrocircuit in- and output and establish core networks for emotions. Subsequent pharmaco- and optogenetic circuit manipulation in combination
with in vivo electrophysiological recordings in Pavlovian fear conditioning will resolve circuit interactions in these networks.
In general, emotions like fear and reward states are represented in a two-dimensional space by their affective valence and arousal (Calder, Lawrence et al. 2001). We therefore hypothesize that emotions are encoded by a set of circuits for positive or negative valence and valence non-specific circuits for arousal, and that their relative activity determines emotional states and drives fear avoidance and reward-seeking behavioral responses. We will address this by comparing where pathways of fear and reward diverge and converge. The results will reveal how valence and intensity, the two principle dimensions of emotions, are represented in emotion circuits.
- Figure 2 (Click to view legend)
Genetic and pharmacological modulation of emotional states
While the molecular mechanics by which genes and drugs control neural activity at the cellular level have been worked out in great detail, the circuit mechanics by which this translates into behavior changes have not yet been resolved. We surmise that the circuits identified above serve as an ideal field to study this problem. To this end we will investigate gene effects (anxiolytic and anxiogenic genes and polymorphisms) and the effects of drugs (anxiolytics, addictive drugs) on the activity of the emotion network identified above, and explore how these changes in activity modulate emotional states and behavior. Indeed,
preliminary results suggest that CE circuits are a target of psychoactive drugs, which alter the balance of neural activity in this network (Figure 2B).
Taken together, we hope our research will disclose general principles of the network organization of emotions and provide a framework for understanding the genetics and pharmacology of emotions in health and disease conditions like anxiety disorders or addiction.