Research paper

Anhedonia is associated with higher functional connectivity between the nucleus accumbens and paraventricular nucleus of thalamus

>1 in 5 U.S. adults (22.8 %) reported experiencing a mental illness in the 2021 National Survey on Drug Use and Health conducted by the Substance Abuse and Mental Health Services Administration (Substance Abuse and Mental Health Services Administration, 2022). Current diagnostic criteria in psychiatry seem to have a limited ability to capture the reality of mental illness, including: dimensional symptom spaces, high frequency of comorbidities, and phenotypic fluctuations across time, among other features (Dalgleish et al., 2020). To address this, many researchers have begun to focus on the transdiagnostic features of mental illness, which are factors that cut across traditional diagnostic boundaries. Transdiagnostic features of mental illness may then be studied and related to the underlying neurobiology (Insel et al., 2010). One important transdiagnostic symptom is anhedonia – the diminished capacity to experience pleasure. Understanding anhedonia is critical because it is associated with increased risk of suicide, substance use disorder (specifically opioid use disorder), treatment resistance, and a reduced quality of life (Ducasse et al., 2018; Pizzagalli, 2014; Ritsner et al., 2011; Stull et al., 2022).

Anhedonia is defined as, “the inability to enjoy experiences or activities that normally would be pleasurable” according to the American Psychological Association and was first described by Théodule Ribot in 1896 (American Psychological Association, n.d.; Ribot, 1896). Anhedonia is characterized by decreased reward processing, learning, and memory. Individuals experiencing anhedonia have difficulty initiating behavior in pursuit of reward and have decreased reward responsiveness, though in-the-moment pleasure to reward is often maintained (Pizzagalli, 2010). The nucleus accumbens (NAc) is a key region in understanding anhedonia, as it is critically important to the experience of pleasure and the learning of pleasant stimuli associations(Der-Avakian and Markou, 2012). Reward prediction error via dopaminergic signaling is one well-established mechanism by which the NAc codes incentive properties of cues for learning (Schultz, 1998). Dopamine transmission is therefore important in the motivational aspects of reward that are impacted by anhedonia (Harkness et al., 2022). Meanwhile, the perception of a pleasurable stimulus is driven in part by endogenous opioids in the NAc shell (Peciña and Berridge, 2005). In humans, neuroimaging studies have characterized changes of the functional connectivity of the NAc in adults across mood disorders (Sharma et al., 2017), adolescents with anhedonia (Gabbay et al., 2013), and trauma-exposed individuals (Olson et al., 2018). While the exact cause of changes to the NAc and its circuits in anhedonia is still under investigation, the paraventricular nucleus of thalamus (PVT) is a region highly connected to the NAc that may drive the presentation of anhedonia (Moga et al., 1995; Vertes and Hoover, 2008).

The PVT is of interest to anhedonia research because across rodent studies, the PVT has been shown to play a role in processing salient experiences, broadly (Kooiker et al., 2021). More specifically, several studies in animal models examining the projections between the PVT and NAc suggest that the PVT is important for both aversive and appetitive stimulus processing (De Groote and de Kerchove d'Exaerde, 2021; Millan et al., 2017). In one study supporting the role of PVT in appetitive stimuli processing, optogenetic stimulation of oxytocin receptor-expressing neurons in the PVT that project to the NAc increased food-seeking behavior, providing further evidence for this projection's role in motivation (Ye et al., 2022). Stimulation of PVT glutamatergic glucose transporter (Glut2) expressing neurons projecting to the NAc increased motivated sugar-seeking behavior (Labouèbe et al., 2016). In rats trained with an alcohol reward, lesioning of PVT➔NAcSh projections prevented context-induced reinstatement (Hamlin et al., 2009). In male rodents, the PVT stimulated dopamine release by medium spiny neurons in the NAc (Perez and Lodge, 2018).

Numerous studies have corroborated the role of PVT➔NAc projection in suppressing reward seeking behavior. The optogenetic inhibition of the PVT to NAc projection supported hedonic learning in rodents during a cocaine-conditioned place preference experiment and dopamine and methamphetamine was shown to depress excitatory postsynaptic currents from PVT inputs to the NAc (Christoffel et al., 2021). The PVT to nucleus accumbens shell (NAcSh) neurons had elevated Fos expression following opiate withdrawal in mice and their inhibition impaired the formation and expression of conditioned place aversion, providing evidence for a role in opiate and aversive memory mediation by this projection (Zhu et al., 2016). Activation of corticotropin releasing factor (CRF) producing neurons that project PVT → NAc decrease reward seeking and promote threat avoidance (Engelke et al., 2021). Inhibition of mouse PVT afferents to the NAc led to increased responses rates on an operant task regardless of reward availability, while activation of this projection reduced responses in an operant task where reward was constantly available (Lafferty et al., 2020). This suggests the PVT-NAc projection plays a key role in behavioral suppression and reward seeking suppression. Similarly, inhibition of anterior PVT → NAc projections increased cue-induced sucrose seeking in absence of a reward, only (Do-Monte et al., 2017). The discrepancy between the role of PVT-NAc projections in both appetitive and aversive behavior may be explained by the positive feedback that the PVT is providing to the NAc. Appetitive behavior may be driven by PVT projections to D1 neurons in the NAc, while aversive behavior may be influenced by feedforward inhibition via D2 projections. Indeed, this positive feedback mechanism is thought to describe how the PVT mediates motivational conflict (McNally, 2021). Biological evidence supports multiple information streams between PVT-NAc, as two projections that differ in D2 receptor expression have opposing functions (Beas et al., 2024). Sex differences have been observed in the manifestation of anhedonia induced by early life adversity (ELA) (Levis et al., 2021). ELA leads to sex-dependent activation PVT, which may result in anhedonia in males and increased reward-related behavior in females later in life (Kooiker et al., 2023). Despite the growing research on the PVT and NAc in the context of hedonic experiences, no study to date has addressed the connection between the PVT and NAc in human anhedonia.

While the PVT has been circumscribed in humans using post-mortem histological techniques, studies of the PVT in humans in-vivo have not been possible until recently. Our group has delineated the functional connectivity of the PVT in adults from the Human Connectome Project (HCP) dataset using 3D atlases that have characterized thalamic subnuclei and are employed here. The human PVT was found to be functionally connected to NAc, amygdala, and other analogous nodes to those found in the rodent literature (Kark et al., 2021). In this study, we assessed whether anhedonia is associated with PVT circuitry using functional connectivity measures derived from resting state fMRI. We hypothesized that changes in the PVT-NAc circuit, but not circuits from other midline thalamic nuclei, will be associated with anhedonia symptoms.