Periaqueductal gray afferents synapse onto dopamine and GABA neurons in the rat ventral tegmental area

Abstract

The midbrain central gray (periaqueductal gray; PAG) mediates defensive behaviors and is implicated in the rewarding effects of opiate drugs. Projections from the PAG to the ventral tegmental area (VTA) suggest that this region might also regulate behaviors involving motivation and cognition. However, studies have not yet examined the morphological features of PAG axons in the VTA or whether they synapse onto dopamine (DA) or GABA neurons. In this study, we injected anterograde tracers into the rat PAG and used immunoperoxidase to visualize the projections to the VTA. Immunogold-silver labeling for tyrosine hydroxylase (TH) or GABA was then used to identify the phenotype of innervated cells. Electron microscopic examination of the VTA revealed axons labeled anterogradely from the PAG, including myelinated and unmyelinated fibers and axon varicosities, some of which formed identifiable synapses. Approximately 55% of these synaptic contacts were of the symmetric (presumably inhibitory) type; the rest were asymmetric (presumably excitatory). These findings are consistent with the presence of both GABA and glutamate projection neurons in the PAG. Some PAG axons contained dense-cored vesicles indicating the presence of neuropeptides in addition to classical neurotransmitters. PAG projections synapsed onto both DA and GABA cells with no obvious selectivity, providing the first anatomical evidence for these direct connections. The results suggest a diverse nature of PAG physiological actions on midbrain neurons. Moreover, as both the VTA and PAG are implicated in the reinforcing actions of opiates, our findings provide a potential substrate for some of the rewarding effects of these drugs.

Central Autonomic System

“…These neurons project to the nucleus accumbens (Hasue and Shammah-Lagnado, 2002), are wake active and innervate other forebrain sites involved in arousal (Lu et al, 2006a). The PAG has also been found to project to the ventral tegmental area, a region involved in modulating reward behavior (Geisler et al, 2007;Omelchenko and Sesack, 2010). The PAG innervates areas involved in modulation of nociception, including an input from the ventrolateral PAG to the region of the A7 noradrenergic group (Bajic et al, 2001) and several thalamic regions, VI.…”

Pathological circuit function underlying addiction and anxiety disorders

“…Like the amygdala, the PAG directly connects to the reward sys tem, not only through ascending pathways conveying informa tion about expected aversive events but also via projections to the mesocorticolimbic system, including the VTA 46 . The PAG might thus represent another important hub where interactions between circuits processing aversive and appetitive information occur, thereby regulat ing behavior in ambivalent conditions.…”

An update on the connections of the ventral mesencephalic dopaminergic complex

“…1B–D), also comprise combinations of DA, GABA and GLU neurons (Moriizumi et al, 1992, Rogriguez and Gonzalez-Hernandez, 1999; Nair-Roberts et al, 2008; Geisler et al, 2007; Omelchenko and Sesack, 2010; Yamaguchi et al, 2013). The SNc and RRF are reported to contain approximately 29% and 58% GABA neurons, respectively, but apparently few GLU neurons (Nair-Roberts et al, 2008).…”

“…Interestingly, these data leave little room for significant co-expression of GLU and DA in the SNc and RRF. The PAG also contains GLU (Geisler et al, 2007) and GABA projection neurons (Omelchenko and Sesack, 2010). …”