ORCID
https://orcid.org/0000-0001-9070-8552
Date of Award
11-29-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Chronic pain is a debilitating neurological disorder that affects hundreds of millions of individuals worldwide. It is associated with cognitive symptoms such as cognitive inflexibility, which is defined as the inability to adaptively update behavior in response to changing environmental conditions. To date, there are no effective treatments for these symptoms, even though they substantially contribute to the decreased quality of life of chronic pain patients and are associated with reduced efficacy of pain management strategies. Therefore, understanding the neural circuit adaptations that drive cognitive symptoms of chronic pain, like cognitive inflexibility, is essential for improving existing treatments for this disorder. A growing body of evidence suggests that the emergence of a hypodopaminergic state following chronic pain may underlie these affective and cognitive symptoms. Dopamine mediates valence encoding and action selection within the nucleus accumbens shell (NAcSh) by modulating the excitability of medium spiny neurons (MSNs; the principal cell type of the NAcSh), which express either D1- or D2-dopaminergic receptor. Additionally, dopamine modulates excitatory synaptic inputs to these MSNs, such as the input from the medial prefrontal cortex (mPFC). As the mPFC to NAcSh pathway is essential for forming reward associations and generating goal-directed behavior, a chronic pain-associated hypodopaminergic state could disrupt the function of the mPFC–NAcSh pathway and lead to impaired reward learning or changes in goal-directed behavior. In this dissertation, we conducted all testing using a rodent model of chronic neuropathic pain, the spared nerve injury (SNI) model. We first characterized the intrinsic excitability and synaptic transmission of D1- and D2-MSNs in the NAcSh following SNI induction. In particular, we examined the excitatory inputs from the prelimbic (PL) and infralimbic (IL) subregions of the mPFC to the NAcSh. Our data show that SNI leads to synaptic and intrinsic adaptations selectively on D1-MSNs, where a depolarized resting membrane potential is compensated by increases in action potential threshold and rheobase, resulting in no overall change in excitability. In addition, SNI also leads to a decrease in excitatory transmission, as shown as a reduced miniature excitatory postsynaptic current (mEPSC) amplitude, to the D1-MSNs that are not driven by altered PL or IL inputs. Consistent with the lack of functional alterations at the PL/IL to NAcSh pathway, we found that SNI mice showed intact cognitive flexibility in the deterministic reversal task when a timeout punishment was introduced. In other words, they were able to flexibly adapt responses to follow reward contingency changes. This suggests that the selective deficit in the unpunished reversal learning task was driven not by the inability to flexibly update behavior but by a reduction in effort to engage with the task. By further examining the effort allocation strategies of the SNI mice using a resetting progressive ratio (rPR) task, we confirmed that SNI mice minimized effort expenditure while securing the necessary caloric requirement for survival. This altered effort allocation strategy is potentially driven by long-term changes in the mesolimbic circuit, as acute analgesia was not able to promote effort exertion in SNI mice. Overall, our behavioral results align with the self-regulation theory of pain-associated cognitive deficits, which posits that pain leads to resource conservation and diminishes motivation to engage in cognitively demanding tasks. Collectively, we demonstrate altered excitatory synaptic transmission on the D1-MSNs of the NAcSh, along with reduced effort exertion that could potentially drive the manifestation of cognitive inflexibility in a chronic neuropathic state. This work advances our understanding of the neural mechanisms underlying chronic pain-induced cognitive deficits and highlights the importance of targeting effort-related behavioral adaptations in the treatment of chronic pain and its associated cognitive symptoms.
Language
English (en)
Chair and Committee
Meaghan Creed
Committee Members
Jeff Beeler; Ream Al-Hasani; Robert Gereau; Simon Haroutounian
Recommended Citation
Chang, Yu-Hsuan, "Accumbal Plasticity and Associated Behavioral Adaptations in the Spared Nerve Injury Model of Chronic Neuropathic Pain" (2024). Arts & Sciences Electronic Theses and Dissertations. 3359.
https://openscholarship.wustl.edu/art_sci_etds/3359