Research Article

Amygdala ensembles encode behavioral states

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Science  19 Apr 2019:
Vol. 364, Issue 6437, eaav8736
DOI: 10.1126/science.aav8736

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Neuron activity across the brain

How is it that groups of neurons dispersed through the brain interact to generate complex behaviors? Three papers in this issue present brain-scale studies of neuronal activity and dynamics (see the Perspective by Huk and Hart). Allen et al. found that in thirsty mice, there is widespread neural activity related to stimuli that elicit licking and drinking. Individual neurons encoded task-specific responses, but every brain area contained neurons with different types of response. Optogenetic stimulation of thirst-sensing neurons in one area of the brain reinstated drinking and neuronal activity across the brain that previously signaled thirst. Gründemann et al. investigated the activity of mouse basal amygdala neurons in relation to behavior during different tasks. Two ensembles of neurons showed orthogonal activity during exploratory and nonexploratory behaviors, possibly reflecting different levels of anxiety experienced in these areas. Stringer et al. analyzed spontaneous neuronal firing, finding that neurons in the primary visual cortex encoded both visual information and motor activity related to facial movements. The variability of neuronal responses to visual stimuli in the primary visual area is mainly related to arousal and reflects the encoding of latent behavioral states.

Science, this issue p. eaav3932, p. eaav8736, p. eaav7893; see also p. 236

Structured Abstract

INTRODUCTION

Affective or metabolic states, such as anxiety, stress, or thirst, enable adaptations of perception and the selection of appropriate behaviors to achieve safety or homeostasis. Classically, changes in brain states are associated with thalamocortical circuitry and sensory coding. Yet homeostatic and affective states are associated with complex behavioral, autonomic, and hormonal responses, suggesting that state representations involve brain-wide networks, including subcortical structures such as the amygdala. Previously, amygdala function has been studied mainly in the framework of Pavlovian conditioning, leading to the identification of specific circuit elements that underlie associative plasticity at the single-cell and neural-ensemble levels. However, how internal states engage neuronal ensembles in the basal amygdala, a hub for regulating affective, homeostatic, foraging, and social behaviors via widespread connections with many other brain areas, remains unknown.

RATIONALE

The encoding of states governing self-paced behaviors, including foraging or place avoidance, should engage large neuronal populations, evolve on longer time scales (seconds to minutes), generalize across contexts, and lead to differences in sensory processing and action selection. We therefore used a miniature microscope and longitudinal imaging of amygdala neural activity in freely moving mice performing a series of behavioral paradigms in different contexts across multiple days. We thereby tracked neuronal population activity across distinct behavioral paradigms in which mice exhibited distinct modes of behavior manifesting different internal states.

RESULTS

We tracked amygdala neuronal activity across the open-field test, the elevated plus maze test, and a classical Pavlovian fear-conditioning paradigm. During open-field exploration, two large ensembles of basal amygdala neurons antagonistically conveyed information about an animal’s corner or center location. This population signature of opposing ensemble activity occurred on a slow time scale (seconds), was evident across consecutive days and paradigms, and predicted transitions from exploratory to nonexploratory, defensive states and vice versa. Notably, amygdala ensemble coding did not align with spatial areas generally thought to correspond to global anxiety states (e.g., the open-field corners and the closed arms of the elevated plus maze) but instead reflected moment-to-moment changes in the exploratory or defensive state of the animal. During fear conditioning, sensory responses of amygdala neuronal populations to conditioned (tone) and unconditioned (shock) stimuli were orthogonal to state encoding, demonstrating that fast sensory responses and slow exploratory state dynamics were separately encoded by amygdala networks. Correlations of neural responses to state transitions were largely conserved across major amygdala output pathways to the hippocampus, nucleus accumbens, and prefrontal cortex.

CONCLUSION

Our study reveals two large, nonoverlapping functional neuronal ensembles of the basal amygdala representing internal states. The ensembles are anatomically intermingled and encode opposing moment-to-moment states changes, especially regarding exploratory and defensive behaviors, but do not provide a scalar measure of global anxiety levels.

The amygdala broadcasts state signals to a wider brain network, including cortical and subcortical areas. These signals are likely correlated with diverse aspects of brain state, including anxiety, arousal, sensory processing, and action selection. This extends the current concept of thalamocortical brain-state coding to include affective and exploratory state representations in the amygdala, which have the potential to control state-dependent regulation of behavioral output and internal drives. Our findings provide a low-dimensional amygdala population signature as a trackable measure for the state dependency of brain function and behavior in defined neuronal circuits. It remains to be tested whether a maladaptive bias in neuronal state coding in the basolateral amygdala contributes to behavioral and physiological alterations in animal disease models.

Amygdala ensembles encode behavioral states.

Two large, antagonistic basal amygdala neural ensembles signal opposite behavioral states conserved across different behavioral paradigms and contexts. This neural state signature separates exploratory and nonexploratory, defensive behaviors (dashed line) on a moment-to-moment basis, does not align with global anxiety levels (red clusters, high anxiety; blue clusters, low anxiety), is orthogonal to sensory responses, and is broadcast to a wider brain network.

Abstract

Internal states, including affective or homeostatic states, are important behavioral motivators. The amygdala regulates motivated behaviors, yet how distinct states are represented in amygdala circuits is unknown. By longitudinally imaging neural calcium dynamics in freely moving mice across different environments, we identified opponent changes in activity levels of two major, nonoverlapping populations of basal amygdala principal neurons. This population signature does not report global anxiety but predicts switches between exploratory and nonexploratory, defensive states. Moreover, the amygdala separately processes external stimuli and internal states and broadcasts state information via several output pathways to larger brain networks. Our findings extend the concept of thalamocortical “brain-state” coding to include affective and exploratory states and provide an entry point into the state dependency of brain function and behavior in defined circuits.

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