Structure-function properties of mouse forebrain local and long-distance GABAergic connections in acute pain and pain chronicity

Inhibitory interneurons maintain an intricate control of activity in the brain and carry out critical functions in cognitive, emotional as well as sensory tasks. As with several neurological disorders, an imbalance between excitation and inhibition has been long proposed to underlie the induction and maintenance of chronic pain. In the context of pain, inhibition has been well-studied in the spinal circuits, with well-characterized contributions from both main inhibitory neurotransmitters, namely γ-aminobutyric acid-releasing (GABA) and glycine being the focus of many studies. Disinhibition in the spinal cord has been proposed as a mechanism for chronic pain, particularly in the context of nerve injury-induced mechanical allodynia. 

In contrast to the pronounced focus on inhibitory control of nociceptive processing in the spinal cord, very little is known about how inhibition shapes cortical neuronal activity in pain states. Indeed, work on inhibition of pain at supraspinal sites has been largely focused on opioidergic control and cannabinoidergic modulation. In contrast, the nature and functional roles of specific inhibitory circuits within the cortex and its interactions with subcortical and limbic structures in controlling pain has not been studied.

GABA is the main inhibitory neurotransmitter in the brain and a huge diversity of GABAergic neurons with specific functions is emerging in recent studies. Accordingly, important insights are being uncovered on the functions of GABAergic neurons in place recognition and spatial memory. Studies on GABAergic control of sensory perception are also currently the subject of intense scientific interest, but have so far been largely limited to analyses in the visual inputs in the primary visual cortex and tactile sensory inputs in the barrel cortex; in contrast, control of pain has not been studied so far.

Although a majority of GABAergic interneurons modulate local activity, there is increasing evidence that long-range GABAergic neurons couple brain regions that are functionally related. Often the coupling is bidirectional. For instance, such bidirectional GABAergic projections were found to connect the septum and hippocampus or the entorhinal cortex and the hippocampus. The detailed circuitry and functional contributions of long-range GABAergic projections are only beginning to be fully worked out. However, the existence and nature of long-range GABAergic connections in pain-related networks in the brain has not been addressed so far.

The Monyer group has a long, established record in the study of neural circuits underlying learning, memory and other cognitive functions, with an emphasis on elucidating structure-function attributes of specific interneuron classes and circuits. The R. Kuner group has a long-standing record in addressing molecular, cellular and network mechanisms underlying the transition between acute pain and chronic pain.

Together, we aim to study inhibitory mechanisms within cortico-cortical circuits and their connections with subcortical structures, most notably with the striatum, and with parts of the limbic system ex-vivo as well as in vivo in awake, behaving mice. Optogenetic and genetic manipulations will be functionally assessed for their impact on pain behavior in vivo in models of nociception, acute pain and chronic inflammatory and neuropathic pain.

 

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