| Summary: |
Stressful conditions including chronic pain have been recognized as being major disruptors of prefrontal cortex (PFC) circuits. The current view is that chronic pain can contribute to imbalance of PFC dopaminergic signaling and that may produce "noise" in local PFC networks and abnormal output to other subcortical structures. It has been hypothesized that sensory overload typical of painful syndromes can contribute to an hypoactivity of mesocortico-limbic dopamine (DA) projections to the PFC, resulting in a PFC hypostimulation and cognitive impairments, in a manner very close to what happens in neurological and psychiatric diseases. Although, less is known about the mechanisms underlying this PFC hypodominergic tone, and this constitutes the main goal of this project in order develop new more effective neural PFC circuit-oriented treatment strategies for reverse pain-related cognitive impairments.
DA modulation of GABAergic transmission in the PFC is thought to be critical for sustaining the transient boost of the neural representations of events necessary for decision-making and working-memory (WM) processes. The neurobiology underlying the modulation of these PFC functions is thought to be mediated by DA ability to enable context relevant inputs to enhance the activity of selective neuronal ensembles. DA action in the PFC includes activation of fast-spiking interneurons, which are a subset of GABAergic interneurons critical for determining the timing and spatial selectivity of pyramidal cells firing. In this regard, the ventral tegmental area stimulation frequently results in suppression of pyramidal cells activity in the PFC, an inhibitory response that matches the temporal course of local PFC fast-spiking interneurons excitation. It has been suggested that fast-spiking interneurons could shape the response pattern of PFC pyramidal neurons to mesocortico-limbic DA drive. At the cellular level, there is ample evidence that part of the inhibitory action of  |
Summary
Stressful conditions including chronic pain have been recognized as being major disruptors of prefrontal cortex (PFC) circuits. The current view is that chronic pain can contribute to imbalance of PFC dopaminergic signaling and that may produce "noise" in local PFC networks and abnormal output to other subcortical structures. It has been hypothesized that sensory overload typical of painful syndromes can contribute to an hypoactivity of mesocortico-limbic dopamine (DA) projections to the PFC, resulting in a PFC hypostimulation and cognitive impairments, in a manner very close to what happens in neurological and psychiatric diseases. Although, less is known about the mechanisms underlying this PFC hypodominergic tone, and this constitutes the main goal of this project in order develop new more effective neural PFC circuit-oriented treatment strategies for reverse pain-related cognitive impairments.
DA modulation of GABAergic transmission in the PFC is thought to be critical for sustaining the transient boost of the neural representations of events necessary for decision-making and working-memory (WM) processes. The neurobiology underlying the modulation of these PFC functions is thought to be mediated by DA ability to enable context relevant inputs to enhance the activity of selective neuronal ensembles. DA action in the PFC includes activation of fast-spiking interneurons, which are a subset of GABAergic interneurons critical for determining the timing and spatial selectivity of pyramidal cells firing. In this regard, the ventral tegmental area stimulation frequently results in suppression of pyramidal cells activity in the PFC, an inhibitory response that matches the temporal course of local PFC fast-spiking interneurons excitation. It has been suggested that fast-spiking interneurons could shape the response pattern of PFC pyramidal neurons to mesocortico-limbic DA drive. At the cellular level, there is ample evidence that part of the inhibitory action of DA in the PFC is due to an enhancement of local GABAergic tone. In fact, GABAergic PFC interneurons do express DA receptors, and fast-spiking interneurons excitability becomes positively modulated by PFC D1 and D2 receptors. Thus, a fine tuning between local PFC GABAergic transmission and pyramidal cells firing by DA has been proposed to play a pivotal role in the regulation of WM processes as disruptions of such interactions are implicated in pathophysiology of cognitive deficits.
In this project, we will take in advantage the extensive experience gathered in neurophysiology in awake behaving animals to associate optogenetic stimulation in order to modulate selectively PFC dopaminergic tone. Specifically, we want to know if the modulation of the mesocortico-limbic dopaminergic drive is able to revert the pain-related imbalance of the PFC inhibitory tone, and if this circuit-directed manipulation produces an impact on nociceptive responses and cognitive performance. |