Abstract
Frontal-subcortical circuit dysfunction is commonly associated with apathy, a neuropsychiatric sequelae of human immunodeficiency virus type-1 (HIV-1). Behavioral and neurochemical indices of apathy in the nucleus accumbens (NAc), a key brain region involved in frontal-subcortical circuitry, are influenced by the factor of biological sex. Despite evidence of sex differences in HIV-1, the effect of biological sex on medium spiny neurons (MSNs), which are central integrators of frontal-subcortical input, has not been systematically evaluated. In the present study, a DiOlistic labeling technique was used to investigate the role of long-term HIV-1 viral protein exposure, the factor of biological sex, and their possible interaction, on synaptic dysfunction in MSNs of the NAc in the HIV-1 transgenic (Tg) rat. HIV-1 Tg rats, independent of biological sex, displayed profound alterations in synaptic connectivity, evidenced by a prominent shift in the distribution of dendritic spines. Female HIV-1 Tg rats, but not male HIV-1 Tg rats, exhibited alterations in dendritic branching and neuronal arbor complexity relative to control animals, supporting an alteration in glutamate neurotransmission. Morphologically, HIV-1 Tg male, but not female HIV-1 Tg rats, displayed a population shift towards decreased dendritic spine volume, suggesting decreased synaptic area, relative to control animals. Synaptic dysfunction accurately identified presence of the HIV-1 transgene, dependent upon biological sex, with at least 80% accuracy (i.e., Male: 80%; Female: 90%). Collectively, these results support a primary alteration in circuit connectivity, the mechanism of which is dependent upon biological sex. Understanding the effect of biological sex on the underlying neural mechanism for HIV-1 associated apathy is vital for the development of sex-based therapeutics and cure strategies.
Highlights
Apathy, one of the neuropsychiatric sequelae of human immunodeficiency virus type 1 (HIV-1), is operationally defined as the quantitative reduction of self-generated voluntary and purposeful behaviors (Levy and Dubois, 2006)
Sholl analyses were used to determine where dendritic spines were located on the neuron, assessed using spine type (i.e., Thin Spines, Stubby Spines, Mushroom Spines), determined using an observer-assisted automatic classification system in Neurolucida 360, genotype (i.e., HIV-1 Tg vs. Control), biological sex
The distributional shift in the where dendritic spines were located on the neuron was dependent upon both the factor of biological sex and spine type (radii × genotype × sex × spine type interaction (F(2,7165) = 3.2, p ≤ 0.042); Supplementary Figure S1)
Summary
One of the neuropsychiatric sequelae of human immunodeficiency virus type 1 (HIV-1), is operationally defined as the quantitative reduction of self-generated voluntary and purposeful (goal-directed) behaviors (Levy and Dubois, 2006). Given the prevalence of apathy in HIV-1 seropositive individuals, there is a critical need to elucidate the structural loci for the actions of HIV-1 viral proteins on goal-directed behaviors. Frontal-subcortical circuit dysfunction is commonly associated with impaired executive functioning (including alterations in sustained attention and memory) and apathy (review, Bonelli and Cummings, 2007). The anterior cingulate circuit, considered one of the behaviorally relevant frontal-subcortical circuits, is more directly related to motivational alterations (Bonelli and Cummings, 2007). Neurons from the anterior cingulate cortex (ACC) send projections to the ventral striatum, including the nucleus accumbens (NAc; Selemon and Goldman-Rakic, 1985), which subsequently innervate the globus pallidus interna, ventral pallidum and rostrodorsal substantia nigra (Critchley, 2005)
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