Determination of circuit-specific morphological adaptations in ventral tegmental area dopamine neurons by chronic morphine

Abstract

Chronic opiate exposure induces neuroadaptations in the mesocorticolimbic system including ventral tegmental area (VTA) dopamine (DA) neurons, whose soma size is decreased following opiate exposure. Yet it is now well documented that VTA DA neurons are heterogeneous, with notable differences between VTA DA neurons based on their projection target. Therefore, we sought to determine whether chronic morphine induced similar changes in the morphology of VTA DA neurons that project to the nucleus accumbens (NAc) and prefrontal cortex (PFC). We utilized Cre-dependent retrograde viral vectors in DA Cre driver lines to label VTA DA neurons that projected to NAc and PFC and assessed neuronal soma size. Consistent with previous data, the soma size of VTA DA neurons that projected to the NAc medial shell was decreased following morphine exposure. However, soma size of VTA DA neurons that projected to the NAc core was unaltered by morphine. Interestingly, morphology of PFC-projecting VTA DA neurons was also altered by morphine, but in this case soma size was increased compared to sham controls. Differences in basal soma size were also noted, suggesting stable differences in projection-specific morphology in addition to drug-induced changes. Together, these data suggest morphine-induced changes in VTA DA morphology occur within distinct VTA DA populations and that study of opiate-induced structural plasticity of individual VTA DA subcircuits may be critical for understanding addiction-related behavior.Electronic supplementary materialThe online version of this article (10.1186/s13041-019-0435-6) contains supplementary material, which is available to authorized users.

TRPC1/4/5 channels contribute to morphine‐induced analgesic tolerance and hyperalgesia by enhancing spinal synaptic potentiation and structural plasticity

“…5,6 However, whether chronic morphine treatment leads to structural plasticity in the spinal cord is not fully understood, although much evidence showed that morphine addiction alters the density of dendritic spines in several brain regions, including nucleus accumbens (NAc), medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and hippocampus. [46][47][48][49] In the present study, we observed for the first time that repetitive administration of morphine produced a prominent remodeling of synaptic dendritic spines in superficial spinal dorsal horn neurons, as characterized by increased spine density as well as spine morphological changes. Combined deletion of TRPC1, TRPC4, and TRPC5 proteins dampens both spinal spine remodeling and synaptic LTP induced by chronic morphine treatment, which provides a novel mechanistic basis for morphine-induced hyperalgesia and analgesic tolerance.…”

“…Opioid‐induced spinal LTP at nociceptor synapses in the spinal cord is now considered to be an essential contributor to opioid‐induced hyperalgesia, and may also analgesic tolerance 5,6 . However, whether chronic morphine treatment leads to structural plasticity in the spinal cord is not fully understood, although much evidence showed that morphine addiction alters the density of dendritic spines in several brain regions, including nucleus accumbens (NAc), medial prefrontal cortex (mPFC), ventral tegmental area (VTA), and hippocampus 46‐49 . In the present study, we observed for the first time that repetitive administration of morphine produced a prominent remodeling of synaptic dendritic spines in superficial spinal dorsal horn neurons, as characterized by increased spine density as well as spine morphological changes.…”

Sox6 expression distinguishes dorsally and ventrally biased dopamine neurons in the substantia nigra with distinctive properties and embryonic origins

“…An inverted projection pattern was previously reported in rodents and primates ( Fallon and Moore, 1978 ; Gerfen, 1985 ; Haber et al, 2000 ), but it has not been observed consistently across all studies ( Matsuda et al, 2009 ; Prensa and Parent, 2001 ); therefore, it has not been depicted in recent models of SNc projections to the CP ( Björklund and Dunnett, 2007 ; Vogt Weisenhorn et al, 2016 ). Potential overlap of Sox6 + and Sox6 − axonal arbors as shown here and in a recent study ( Simmons et al, 2019 ), together with the diverging criteria used to define the dorsoventral division of the SNc and the partially intermingled nature of these neurons, all may be reasons for these inconsistent findings. Importantly, these anatomical findings can explain the patterns of striatal innervation observed in PD brains ( Kordower et al, 2013 ); fibers projecting to the medial striatum are likely preserved because they originate from relatively spared Sox6 − neurons in the dSNc, most of which are also Calb1 + .…”

Gene Expression Changes in the Ventral Tegmental Area of Male Mice with Alternative Social Behavior Experience in Chronic Agonistic Interactions

“…The VTA is one of the major sites of dopamine synthesis. The VTA dopaminergic neurons are implicated in the regulation of emotional and motivational behaviors and are involved in the development of psychopathologies including depression [ 50 ], aggression [ 51 ], and addictions [ 52 , 53 ]. So, it was important to check if the prioritized genes could be implicated in VTA dopaminergic signaling.…”