| Chronic neuropathic pain is a debilitating condition that affects about 18% of the population. There are no validated therapies for the condition, and the pain is often intractable. Since persistent pain is the most common reason people seek medical care, neuropathic pain is a huge burden on the health care system. Not only does neuropathy cause intractable pain, but it also leads to cognitive deficits such as depression, anxiety and disruptions in working memory. The goal of this thesis was to explore brain circuits involved in integrating sensory and cognitive information and to learn how they are disrupted in neuropathic pain. The medial prefrontal cortex (mPFC) is central to many of these circuits. The mPFC has been shown to be hypoactive in neuropathic pain, and activating the region can both alleviate pain and improve the associated cognitive symptoms. Here we explore the cellular underpinnings of mPFC hypoactivity and gray matter volume reduction in the spared nerve injury (SNI) neuropathic pain model. Specifically, we found a reduction in spontaneous and evoked glutamatergic activity, a reduction in ambient glutamate, and a reduction in dendritic length and branching of layer 5 pyramidal neurons one week after SNI. We further explored the contributions of two specific input pathways to mPFC dysfunction. We show that the medial dorsal thalamic (MD Th) input is disrupted both in excitatory drive and recruitment of inhibitory activity. This likely alters spike timing of mPFC neurons and leads to thalamo-cortical dysrhythmia, a hallmark of neuropathic pain. The ventral hippocampal (vHipp) input is also disrupted, with an altered paired pulse ratio that suggests a reduction in presynaptic release probability. This alteration likely contributes to neuropathy-induced impairments in working memory and emotional control of pain. |
