Biology subjects

Anderson, L. G.

Publications and source records attributed to Anderson, L. G..

3 recordsLinked to original sources

bioRxiv2026

D2 autoreceptors gate vulnerability to cocaine use disorder

A defining feature of substance use disorder is that repeated drug use does not always lead to addiction, motivating the search for biomarkers of vulnerability1. Reduced striatal dopamine D2/3 receptor availability is a robust PET correlate of problematic stimulant use2-5, but the signal may reflect high endogenous dopamine level, and it conflates presynaptic D2 autoreceptors on dopamine axons with postsynaptic D2/3 heteroreceptors on striatal projection neurons. We dissociated these contributions using cell type-specific Drd2 haploinsufficiency in dopamine neurons (autoD2KD), D2-expressing medium spiny neurons (MSN-D2KD), or both. Autoreceptor haploinsufficiency (autoD2KD) weakened presynaptic control of dopamine release, enhanced phasic gain, and prolonged cocaine-evoked dopamine elevations. This was accompanied by a hyper-exploratory trait and altered cocaine adaptation. Specifically, autoD2KD mice showed greater cocaine-seeking behavior, despite intact responses to sucrose reward and punishment. Although all genotypes showed graded reductions in striatal D2/3 binding, D1-like compensations diverged, resulting in different D1:D2/3 ratio in the striatum. The clinical implication is that striatal D1 density and D1:D2/3 balance may emerge as critical biomarkers for distinguishing cell-type-specific D2 reductions relevant to addiction vulnerability.

neuroscience↗

bioRxiv2025

Early life adversity increases striatal dopamine D1 receptor density and promotes social alcohol drinking in mice, especially males

The brains reward circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. Adverse experiences early in life can increase vulnerability to substance use disorders, likely through alterations to this circuitry. Yet, the precise neurobiological mechanisms by which early life adversity acts are incompletely characterized. In this study, we used a limited bedding and nesting (LBN) paradigm as a translationally relevant model of early life adversity in genetically-identical C57BL/6J mice. After LBN-rearing, we assess the lasting behavioral and neurobiological impacts of this experience in adulthood. In robust sample sizes, our results validated previous findings of increased risk avoidance, enhanced acute response to alcohol, and greater voluntary alcohol drinking in socially-housed LBN-reared mice, especially males. Further, using autoradiography, we found LBN-reared mice had increased striatal D1-like receptor binding, skewing D1-to D2-like receptor balance relative to cross-fostered controls. However, after voluntary alcohol drinking, we found a strong downregulation in D1-like, and some D2-like, receptor binding, negating pre-existing differences in striatal dopamine receptor binding. We posit that via both transcriptional and post-transcriptional mechanisms, LBN-rearing upregulates striatal D1-receptor density and alters risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. Together, these findings reveal specific neurobiological mechanisms that promote alcohol consumption following early life adversity and suggest complex interactions between early life adversity, sex-related factors, and dopamine receptor regulation in contributing to alcohol use disorder (AUD) vulnerability.

neuroscience↗

bioRxiv2025

Cholinergic-dependent dopamine signals in mouse dorsal striatum are regulated by frontal but not sensory cortices

Everyday decisions depend on linking sensory stimuli with actions and outcomes. The striatum supports these sensorimotor associations through dopamine-dependent plasticity. Thus, the timing and magnitude of dopamine release is critical for learning. Recent work has characterized a local striatal microcircuit in which cholinergic interneurons (CINs) modulate dopamine release via acetylcholine activation of nicotinic receptors on dopamine axons. Here, we show that visual stimuli evoke dopamine responses in the dorsomedial striatum through this cholinergic-dependent mechanism. Using anatomical and functional methods to identify which pathways elicit these signals, we found that visual and auditory cortices that project to the dorsomedial striatum lack robust connectivity to CINs and were unable to drive cholinergic-dependent dopamine release. In contrast, frontal cortical regions, including the prelimbic and anterior cingulate cortices, strongly recruited CINs and acetylcholine, producing robust dopamine release both ex vivo and in vivo. These frontal corticostriatal projections are activated by visual stimuli, representing a possible pathway by which visual information reaches the dorsomedial striatum to evoke dopamine. These findings reveal a fundamental distinction between sensory and frontal cortical inputs to the striatum, demonstrating that only the latter evoke cholinergic-dependent dopamine signaling. This work establishes a framework for understanding how cortical circuits shape striatal dopamine to support reinforcement learning.

neuroscience↗