Jamie Maguire, PhD
Kenneth and JoAnn G. Wellner Professor
Department of Neuroscience
Tufts University School of Medicine
(Sept. 14, 2021)
Affective Switching: Understanding the Relationship Between Network and Behavioral States
For a person with chronic stress, it can be hard — sometimes impossible — to break the stress-anxiety-stress loop. Suddenly everything in life becomes stressful, even in normal, everyday situations. Dr. Maguire presented her work demonstrating that chronic stress can have an impact on neuronal signal patterns in an area of the brain known as the basolateral amygdala, switching the signal patterns from a healthy to an unhealthy state. Her lab has identified key components of the switch from healthy to unhealthy states in the networks of cells in the basolateral amygdala, including interneurons responsible for the switching and modulators that could be used to jumpstart the highjacked networks back to healthier patterns of activity. Dr. Maguire suggests that these changes due to chronic stress may be a cause of psychiatric problems that often go hand in hand with epilepsy.
Emerging evidence demonstrates that network states are capable of driving behavioral states. Recent collaborative work between the Maguire and Reijmers labs at Tufts University School of Medicine has demonstrated that signature patterns of oscillations in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) have been shown to correlate with the behavioral expression of fear. Further, we demonstrate that driving specific patterns of oscillations in the BLA using optogenetic approaches is sufficient to modify the behavioral expression of fear. This presentation entitled "Affective switching: understanding the relationship between network and behavioral states" presented recent data from the Maguire Lab demonstrating that chronic stress is capable of corrupting BLA network states, biasing the network towards the unhealthy network and behavioral state. These findings further our understanding of how the network transitions between states and impact behavior under physiological and pathological conditions.
Fundamental to furthering our understanding of how network states influence behavioral states is increasing our understanding of how the network transitions between different network states. Our laboratory demonstrated that parvalbumin-positive (PV) interneurons are critical for orchestrating oscillations in the BLA. Interestingly, these neurons express a high density of δ subunit-containing GABAA receptors (δGABAARs), which mediate tonic GABAergic inhibition and confer neurosteroid sensitivity. We propose that tonic GABAergic inhibition in interneurons is ideally suited to modulate the pattern of network activity in the BLA. We also demonstrate that actions of positive allosteric modulators (PAMs) on δGABAARs, such as allopregnanolone and SAGE-516, are capable of modulating network and behavioral states. We demonstrate that chronic stress corrupts BLA network activity, biasing the network towards the unhealthy state, and treatment with SGE-516 is capable of preventing or restoring the healthy network and behavioral state following chronic stress exposure.
Finally, we demonstrate that the loss of PV interneurons in chronically epileptic mice is enough to corrupt BLA network activity, which is associated with deficits in behavioral states, including an increase in avoidance behaviors, increased learned helplessness, and increased behavioral expression of fear. This may represent a mechanism contributing to the high incidence of psychiatric comorbidities and epilepsy. The presentation also featured collaborative work between the Maguire Lab and the Paradis lab at Brandeis demonstrating the antiseizure effects of Sema4D, which increases inhibitory synapses, and restores diazepam sensitivity in a model of pharmacoresistant status epilepticus. Future studies will investigate the ability of enhancing inhibitory neurotransmission in the BLA on chronic epilepsy and associated psychiatric comorbidities.
Presenting this emerging work to investigators at the Volen National Center for Complex Systems provided me the rare and privileged opportunity to get input on this work from experts on GABAergic neurotransmission, homeostasis and plasticity, circuits and network rhythms.