Date of Award

Spring 5-15-2021

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Understating the function of neural circuits and the state-depended adaptations within them is one of the fundamental aims in the field of neuroscience. With recent technical developments in monitoring circuit dynamic, such as calcium (Ca2+) imaging, visualizing synaptic connections using viral approaches and manipulating neuronal activity in cell-specific manner such as optogenetic and chemogenetics, we are now able to mechanistically link the activity and function of neural circuits with behavioral outcomes.Using the above-mentioned techniques, I demonstrate that pain induces somatic adaptations in the Ventral Tegmental Area (VTA) dopamine (DA) neurons to drive anhedonia-like behaviors. Pain is a complex phenomenon composed of sensory and emotional-affective components. Common line of treatments for pain are opioids whose efficacy diminishes as pain changes from acute to chronic. As pain persists, the presence of negative affective states can lead to the development of negative emotional states such as dysphoria, anhedonia and anxiety. These co-morbid disturbances can lead to depression and opioid misuse, consequently escalating into life threatening events such as suicide attempts or accidental opioid overdoses. Emerging evidence from human and preclinical studies show deficits in emotional decision making, reward evaluation and reward seeking, or motivation in pain states. These alterations in reward processing and decreased motivation represent key components of pain-induced negative affective states that can lead to the development of anhedonia and depression. Within the mesolimbic reward pathway, VTA DA neurons projecting to the nucleus accumbens (NAc) have a prominent role in reward processing and motivated behavior. One of the main mediators of the VTA DA neuron activity are inhibitory GABAergic inputs. These inhibitory GABAergic inputs arise from the rostromedial tegmental nucleus (RMTg), NAc, ventral pallidum (VP), and bed nucleus of stria terminalis (BNST), among others, and make up a majority of the synaptic input. Furthermore, RMTg GABAergic inputs are highly controlled by the  opioid receptor (MOR) system which is downregulated in the presence of pain as demonstrated by previous work form our lab and others. Thus, I hypothesized that pain induces adaptations in the VTA DA by disruption of MOR function at the presynaptic GABAergic terminals in the VTA, consequently leading to anhedonia-like behaviors. Indeed, I found that pain increases RMTg inhibitory tone onto VTA DA neurons making them less excitable. In line with this finding a decreased activity of VTA DA neurons is associated with reduced motivation for natural rewards, consistent with anhedonia-like behavior. Furthermore, I report that enhancing activity of NAc-projecting DA neurons in the VTA using chemogenetics is sufficient to overcome pain-induced reduction in motivated behavior. I also demonstrate that the decrease in sucrose consumption induced by the presence of pain can be overcome by increasing the concentration of the sucrose reward, further suggesting impaired hedonic responses in pain. Lastly, I was able to mimic the effects of pain on sucrose consumption by chemogenetic stimulation of RMTg GABA neurons. Overall, the results generated in this dissertation represent a crucial step in understanding the neural circuit mechanisms underlying the emotional component of pain and may provide novel targets for the treatment of pain-induced negative affect. It is well known that we are facing a pain crisis. In addition to that about 30 percent of pain patients prescribed opioids for their symptoms misuse them. Furthermore, even with the current maintenance medications and treatments, 40 to 60 percent of patients relapse after periods of abstinence. Long term maintenance of associations between the reinforcing effects of the drug and the environment in which they are administered are a leading cause of relapse. Numerous studies indicate that glutamatergic transmission in the dHPC is crucial for the formation of the learned associations between the rewarding effects of opioids and the context in which they are given. Additionally, dHPC projects to NAc, a key area for processing of cue-predicted reward related behaviors. Thus, I hypothesized that dHPC is necessary for relapse in drug seeking behaviors induced by drug-associated contextual cues. To assess the role of dHPC in reinstatement of opioid drug-seeking I used a chemogenetic approach to selectively silence dHPC excitatory neurons. Findings presented in this dissertation demonstrate that silencing excitatory dHPC neurons during re-exposure to drug-context significantly attenuates drug-seeking reinstatement. In addition, silencing dHPC did not alter either short-term or long-term memory as measured using an object location task. This result demonstrates that the observed attenuation of reinstatement is not due memory retrieval impairment but rather to a selective disruption of drug-reward association. While these findings uncover the necessity of dHPC in cue induced reinstatement, the exact inputs mediating the activity of dHCP are yet to be uncovered. To this end I am utilizing viral approaches and chemogenetics to further dissect the circuit driving contextual-cue induced reinstatement of drug-seeking.


English (en)

Chair and Committee

Jose A. Morón-Concepción

Committee Members

Ream Al-Hasani, Michael R. Bruchas, Tamara Hershey, Ilya Monosov,