Changes in behavioral states let us rapidly adapt and react to opportunities and dangers in an ever-changing environment, and are thus critical to ensure survival. The behavioral state we are most interested in is the high anxiety state, which allows animals to assess risks while minimizing exposure to potential threats. The anxious state involves many adaptations, including avoidance of danger, increases in heart rate and changes in stress-related hormones in the blood stream. Furthermore, anxiety levels modulate changes in other behaviors as well, such as eating and sleeping. Although it is known that high anxiety is accompanied by multiple manifestations, little is known about the specific neural circuits that control each of symptom. How does anxiety affect eating or aggression? Are physiological and behavioral symptoms of anxiety modulated by the same circuits?
Our goal is to answer questions such as these by dissecting how interactions between different brain regions orchestrate the numerous symptoms of the anxious state using mice as a model organism. To achieve an integrated view of these phenomena we use a wide range of techniques, including electrophysiology, behavior, fiber photometry and optogenetics. The combination of these powerful techniques allows us to monitor and manipulate neural activity at both the microcircuit and long-range connection levels, providing causal relationships between neural activity and specific behaviors in mice.
Highlights of Previous Discoveries
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Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety
The ventral hippocampus, unlike its dorsal counter- part, is required for anxiety-like behavior. The means by which it acts are unknown. We hypothesized that the hippocampus synchronizes with downstream targets that influence anxiety, such as the medial prefrontal cortex (mPFC). To test this hypothesis, we recorded mPFC and hippocampal activity in mice exposed to two anxiogenic arenas. Theta- frequency activity in the mPFC and ventral, but not dorsal, hippocampus was highly correlated at base- line, and this correlation increased in both anxiogenic environments. Increases in mPFC theta power pre- dicted avoidance of the aversive compartments of each arena and were larger in serotonin 1A receptor knockout mice, a genetic model of increased anxiety-like behavior. These results suggest a role for theta-frequency synchronization between the ventral hippocampus and the mPFC in anxiety. They are consistent with the notion that such synchronization is a general mechanism by which the hippocampus communicates with downstream structures of behavioral relevance.
Synchrony of neural activity between the ventral hippocampus and the medial prefrontal cortex (mPFC) predicts avoidance of risk. Adhikari et al., Neuron, 2010 [pdf]
Single Units in the Medial Prefrontal Cortex with Anxiety-Related Firing Patterns Are Preferentially Influenced by Ventral Hippocampal Activity
The medial prefrontal cortex (mPFC) and ventral hippocampus (vHPC) functionally interact during innate anxiety tasks. To explore the consequences of this interaction, we examined task-related firing of single units from the mPFC of mice exploring stan- dard and modified versions of the elevated plus maze (EPM), an innate anxiety paradigm. Hippocampal local field potentials (LFPs) were simultaneously monitored. The population of mPFC units distin- guished between safe and aversive locations within the maze, regardless of the nature of the anxiogenic stimulus. Strikingly, mPFC units with stronger task- related activity were more strongly coupled to theta-frequency activity in the vHPC LFP. Lastly, task-related activity was inversely correlated with behavioral measures of anxiety. These results clarify the role of the vHPC-mPFC circuit in innate anxiety and underscore how specific inputs may be involved in the generation of behaviorally relevant neural activity within the mPFC.
The mPFC may use hippocampal input to differentiate safe and dangerous locations. Adhikari et al., Neuron, 2011 [pdf]
Diverging Neural Pathways Assemble a Behavioural State from Separable Features in Anxiety
Behavioural states in mammals, such as the anxious state, are char- acterized by several features that are coordinately regulated by diverse nervous system outputs, ranging from behavioural choice patterns to changes in physiology (in anxiety, exemplified respectively by risk-avoidance and respiratory rate alterations)1,2. Here we investigate if and how defined neural projections arising from a single coordinating brain region in mice could mediate diverse features of anxiety. Integrating behavioural assays, in vivo and in vitro electrophysiology, respiratory physiology and optoge- netics, we identify a surprising new role for the bed nucleus of the stria terminalis (BNST) in the coordinated modulation of diverse anxiety features. First, two BNST subregions were unex- pectedly found to exert opposite effects on the anxious state: oval BNST activity promoted several independent anxious state fea- tures, whereas anterodorsal BNST-associated activity exerted anxiolytic influence for the same features. Notably, we found that three distinct anterodorsal BNST efferent projections—to the lat- eral hypothalamus, parabrachial nucleus and ventral tegmental area—each implemented an independent feature of anxiolysis: reduced risk-avoidance, reduced respiratory rate, and increased positive valence, respectively. Furthermore, selective inhibition of corresponding circuit elements in freely moving mice showed opposing behavioural effects compared with excitation, and in vivo recordings during free behaviour showed native spiking patterns in anterodorsal BNST neurons that differentiated safe and anxio- genic environments. These results demonstrate that distinct BNST subregions exert opposite effects in modulating anxiety, establish separable anxiolytic roles for different anterodorsal BNST projec- tions, and illustrate circuit mechanisms underlying selection of features for the assembly of the anxious state.
The extended amygdala uses different outputs to separately control behavioral and physiological symptoms of anxiety. Kim*, Adhikari* et al., Nature, 2013 [pdf]
Basomedial Amygdala Mediates Top-Down Control of Anxiety and Fear
Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high- anxiety states. Lastly, we show that the ventral mPFC–BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.
Activation of the mPFC-amygdala projection suppresses both innate aversion to danger as well as learned fear-conditioned behaviors. Adhikari et al., Nature, 2015 [pdf]