Modulation of dopamine from ventral tegmental area neurons by the LC-REM-OFF and PPT-REM-ON neurons in REMS regulation in freely moving rats.

The role of dopamine (DA)-ergic neurons in ventral tegmental area (VTA) in schizophrenia, depression, hallucinations have been extensively studied. Rapid eye movement sleep (REMS), the closest objective correlate of dream and hallucination, is disrupted during these psychological dysfunctions; however, it was unknown if there is any common neuronal substrate for their regulation. Interactions among locus coeruleus (LC) REM-OFF and pedunculopontine tegmentum (PPT) REM-ON neurons have been reported to regulate REMS in health and diseases. Recently we have reported that PPT neurons modulate VTA and REMS. However, although VTA-DA neurons receive projections from LC and PPT, their role in REMS regulation was unclear. We proposed that the LC and PPT might intermittently modulate VTA-DA neurons and modulate REMS. Male Wistar rats were surgically prepared and electrophysiological wakefulness-sleep-REMS recorded in chronic freely moving condition. We employed RNAi induced downregulation of tyrosine hydroxylase (TH) to evaluate the role of VTA-DA in regulating REMS. We observed that TH-knockdown in VTA decreased REMS in experimental rats, which returned to baseline upon PPT stimulation. Thus, VTA-DA neurons are activated by the REM-ON neurons to modulate REMS, the closest objectively recordable correlate of dreams. In these animals, LC stimulation altered Non-REMS and waking. Based on the findings we have discussed the role of VTA neurochemical circuitry in REMS regulation and their possible implications with REMS-associated dreaming and hallucination in health and diseases.

In the Rat Midbrain, SG2NA and DJ-1 have Common Interactome, Including Mitochondrial Electron Transporters that are Comodulated Under Oxidative Stress.

Scaffold proteins Striatin and SG2NA assemble kinases and phosphatases into the signalling complexes called STRIPAK. Dysfunctional STRIPAKs cause cancer, cerebral cavernous malformations, etc. DJ-1, a sensor for oxidative stress, has long been associated with the Parkinson's disease, cancer, and immune disorders. SG2NA interacts with DJ-1 and Akt providing neuroprotection under oxidative stress. To dissect the role of SG2NA and DJ-1 in neuronal pathobiology, rat midbrain extracts were immunoprecipitated with SG2NA and sixty-three interacting proteins were identified. BN-PAGE followed by the LC-MS/MS showed 1030 comigrating proteins as the potential constituents of the multimeric complexes formed by SG2NA. Forty-three proteins were common between those identified by co-immunoprecipitation and the BN-PAGE. Co-immunoprecipitation with DJ-1 identified 179 interacting partners, of which forty-one also interact with SG2NA. Among those forty-one proteins immunoprecipitated with both SG2NA and DJ-1, thirty-nine comigrated with SG2NA in the BN-PAGE, and thus are bonafide constituents of the supramolecular assemblies comprising both DJ-1 and SG2NA. Among those thirty-nine proteins, seven are involved in mitochondrial oxidative phosphorylation. In rotenone-treated rats having Parkinson's like symptoms, the levels of both SG2NA and DJ-1 increased in the mitochondria; and the association of SG2NA with the electron transport complexes enhanced. In the hemi-Parkinson's model, where the rats were injected with 6-OHDA into the midbrain, the occupancy of SG2NA and DJ-1 in the mitochondrial complexes also increased. Our study thus reveals a new family of potential STRIPAK assemblies involving both SG2NA and DJ-1, with key roles in protecting midbrain from the oxidative stress.

Pedunculo-pontine tegmentum cholinergic REM-ON neurons modulate ventral tegmental neurons to modulate rapid eye movement sleep in rats.

The interaction among the acetylcholine (ACh)-ergic REM-ON neurons in the pedunculo-pontine area (PPT), noradrenergic REM-OFF neurons in locus coeruleus (LC) and GABA-ergic neurons in the regulation of rapid eye movement sleep (REMS) have been studied in relative details; however, many questions including the role of dopamine (DA) remain unanswered. The ventral tegmental area (VTA) is rich in DA-ergic neurons, which have been implicated with schizophrenia and depression, when REMS is significantly affected. Also, some of the symptoms of REMS and these diseases are common. As the ACh-ergic REM-ON neurons in the PPT project to VTA, we proposed that such inputs might affect REMS, dreams and hallucinations. We recorded sleep-wake-REMS in freely moving, chronically prepared rats under three controlled experimental conditions. In different sets of experiments, either the ACh-ergic inputs to the VTA were blocked by local microinjection of Scopolamine (Scop) alone, or, the PPT neurons were bilaterally stimulated by Glutamate (Glut), or, the PPT neurons were stimulated by Glut in presence of Scop into the VTA. It was observed that Glut into PPT and Scop into the VTA significantly increased and decreased REMS, respectively. Additionally, PPT stimulation induced increased REMS was prevented in the presence of Scop into the VTA. Based on these findings we propose that inputs from ACh-ergic REM-ON neurons to VTA increase REMS and it could be a possible circuitry for expressions of hallucinations and dreams.