Synaptic dysfunction is associated with alterations in the initiation of goal-directed behaviors: Implications for HIV-1-associated apathy

Abstract

Individuals living with human immunodeficiency virus type 1 (HIV-1) exhibit an increased prevalence of neuropsychiatric comorbities (e.g., apathy) relative to their seronegative counterparts. Given the profound functional consequences associated with apathy, characterizing the multidimensional neuropsychiatric syndrome, and associated neural mechanisms, following chronic HIV-1 viral protein exposure remains a critical need. HIV-1-associated apathy was examined by quantifying goal-directed behaviors, indexed using voluntary wheel running, during the diurnal and nocturnal cycle. Apathetic behaviors in the HIV-1 transgenic (Tg) rat were characterized by a profound decrease in the number of running bouts during both the diurnal and nocturnal cycle, supporting a prominent deficit in the self-initiation of spontaneous behaviors. Additionally, HIV-1 Tg animals exhibited a decreased reinforcing efficacy of voluntary wheel running during the nocturnal cycle. Following the completion of voluntary wheel running, synaptic dysfunction in medium spiny neurons (MSNs) of the nucleus accumbens core (NAcc) was examined as a potential neural mechanism underlying HIV-1-associated apathy. HIV-1 Tg animals displayed prominent synaptic dysfunction in MSNs of the NAcc, characterized by enhanced dendritic branching complexity and a population shift towards an immature dendritic spine phenotype relative to control animals. Synaptic dysfunction, which accounted for 42.0% to 68.5% of the variance in the number of running bouts, was strongly associated with the self-initiation of spontaneous behaviors. Establishment of the relationship between synaptic dysfunction and apathy affords a key target for the development of novel therapeutics and cure strategies for affective alterations associated with HIV-1.

Keywords: Apathy; Dendritic spines; Goal-directed behaviors; Human immunodeficiency virus type 1; Nucleus Accumbens; Voluntary wheel running.

Figure 1.

(A) Experimental Design Schematic (B) Illustration of the definitions (i.e., number of running bouts, running bout length) utilized for the bout microstructural analysis. Each box represents a one-min bin of activity (i.e., running bout) or disengagement. A running bout was defined as the performance of at least one wheel revolution during consecutive one-min bins. Running bout length was the number of consecutive one-min bins during which an animal was active.

Figure 2.

Motivation for diurnal voluntary wheel running at the macrostructural (i.e., total number of meters run in one session averaged across seven days; A) and microstructural (i.e., number of running bouts, running bout length; B-C) level is illustrated as a function of genotype (HIV-1 Tg vs. Control; ±95% Confidence Intervals). At the macrostructural level, presence of the HIV-1 transgene failed to alter running distance (A). At the microstructural level, HIV-1 Tg animals exhibited prominent motivational alterations, evidenced by a profound decrease in the number of running bouts, relative to control animals (B); observations which support deficits in the self-initiation of spontaneous behaviors. However, once wheel running behavior was initiated, HIV-1 Tg animals displayed a longer running bout length relative to control animals, supporting no deficits in gross-motoric system function (C).

Figure 3.

Observations during the nocturnal voluntary wheel running phase are illustrated as a function of genotype (HIV-1 Tg vs. Control; ±95% Confidence Intervals). At the macrostructural level (i.e., total number of meters run in one session averaged across seven days) presence of the HIV-1 transgene altered the development of voluntary wheel running behavior across time (A). With regards to the number of running bouts, HIV-1 Tg animals exhibited a prominent population shift towards fewer running bouts relative to control animals supporting a deficit in the self-initiation of spontaneous behaviors (B). Furthermore, examination of running bout length in HIV-1 Tg and control animals supports no deficit in gross-motoric system function at either Day 42 (C) or 91 (D).

Figure 4.

After exhibiting a stabilized running distance for at least three weeks during the maintenance phase of nocturnal voluntary wheel running, HIV-1 Tg and control animals were deprived of their running wheels for one, two, and three days. Reinstatement responses, illustrated as a function of genotype (HIV-1 Tg vs. Control; ±95% Confidence Intervals), were examined by providing access to the running wheel for one day after each wheel-locking dose. Both HIV-1 Tg and control animals exhibited a profound burst of rebound running relative to stabilized total running distances at Day 91 (A). In panel A, the green (Control) and blue (HIV-1 Tg) dashed lines in reflect an extension of the 95% confidence interval from the best fit function during the nocturnal voluntary wheel running session. Consistent with observations during the diurnal and nocturnal phase, HIV-1 Tg rats exhibited a prominent decrease in the number of running bouts during the reinstatement response (B). No statistically significant alterations in running bout length were observed during the rebound phase (C).

Figure 5.

Following the completion of voluntary wheel running, the influence of the HIV-1 transgene on neuronal morphology (A-B; ±95% Confidence Intervals), the location of dendritic spines (C) and dendritic spine morphology (D-F) in medium spiny neurons in the nucleus accumbens core was examined. Data are illustrated as a function of genotype (HIV-1 Tg vs. Control). HIV-1 Tg animals exhibited selective alterations in neuronal morphology, characterized by enhanced dendritic branching complexity (B); albeit presence of the HIV-1 transgene failed to significantly alter dendritic arbor complexity (A). Alterations in the location of dendritic spines was evidenced by an increased relative frequency of dendritic spines on branches more proximal to the soma in HIV-1 Tg animals relative to control animals (C). The morphological parameters of dendritic spines in HIV-1 Tg animals were characterized by a bimodal distribution for dendritic spine backbone length (D) and a population shift towards increased dendritic spine head (E) and neck diameter (F) relative to control animals; observations which support a population shift towards a immature dendritic spine phenotype in HIV-1 Tg animals.

Figure 6.

Synaptic dysfunction is strongly associated with the self-initiation of spontaneous behaviors during the diurnal phase (A), nocturnal phase (B), and deprivation/reinstatement phase (C). During the diurnal phase, measures of neuronal morphology explained 42.0% of the variance in the number of running bouts (A). During the nocturnal phase, measures of synaptic dysfunction explained 68.5% of the variance in the number of running bouts (B). During the deprivation/reinstatement phase, 54.5% of the variance in the number of running bouts was explained by measures of synaptic dysfunction (C). Panel (D) reports the results and coefficients from the multiple regression analysis.