Medial septum differentially regulates dopamine neuron activity in the rat ventral tegmental area and substantia nigra via distinct pathways

Abstract

The medial septum (MS) impacts hippocampal activity and the hippocampus, in turn, regulates midbrain dopamine (DA) neuron activity. However, it remains to be determined how MS activation impacts midbrain DA activity. This question was addressed by infusing NMDA (0.75 µg/0.2 µL) into the medial septum of anesthetized male Sprague-Dawley rats and recording dopamine neuron activity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). MS activation increased (71%) the number of spontaneously active DA neurons in the VTA, and decreased (40%) the number of active DA neurons in the SNc. Effects in both the VTA and SNc required the ventral subiculum, but were differentially dependent on cholinergic and GABAergic mechanisms within the vSub and rostral and caudal subregions of the ventral pallidum, respectively. MS activation also decreased amphetamine-induced locomotor behavior, which was dependent on GABAergic inputs to the hippocampus. These findings demonstrate that the MS differentially regulates meso-striatal DA transmission via distinct pathways.

Dysregulation of Midbrain Dopamine System and the Pathophysiology of Schizophrenia

“…Interestingly, the regulation of the midbrain DA system activity by the medial septum in the MAM model of schizophrenia is different from that observed in normal rats (133). Whereas medial septum activation increases VTA DA neuron population activity and inhibits the substantia nigra in the normal rat (130,133), an activation of the substantia nigra and a reduction of the abnormal increased VTA DA neuron population activity in MAM rats to baseline levels was observed (133). A possible explanation for these findings is that, in MAM rats, medial septum activation leads to an increase in the pyramidal neuron inhibition which would mitigate the vHipp hyperactivity (81).…”

“…Thus, the GABAergic and cholinergic projections from the medial septum can differently impact the excitatory-inhibitory balance in the vHipp which could ultimately lead to changes in the VTA DA system. In this context, our group recently found that pharmacological activation of the medial septum by a local infusion of NMDA increased the number of spontaneously active DA neurons in the VTA (130). An opposite effect was found in the substantia nigra.…”

“…Moreover, the effects of medial septum activation on VTA DA neuron population activity were also prevented by the infusion of the muscarinic receptor antagonist scopolamine into the vHipp, suggesting that medial septum cholinergic inputs to the vHipp may be involved in these effects (130). In addition, the inactivation of the anterior portion of the VP blocked the increased VTA DA neuron population activity induced by medial septum activation (130). On the other hand, inactivation of the posterior portion of the VP blocked the suppression of substantia nigra DA neuron population activity by medial septum activation.…”

Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility

“…Interestingly, and in contrast to the effect of WIN55,212-2, there were no observable increases in the locomotor response to amphetamine following adolescent exposure to URB-597 (not shown). One potential reason for this discrepancy is based on recent data from the Grace laboratory suggesting opposing effects of dopamine neuron activity in the VTA and SNc that are mediated by distinct regions of the ventral pallidum ( Bortz and Grace, 2017 ). Thus, the lack of effect on amphetamine-induced behavior may be due to URB-597’s robust targeting of the VP following systemic administration as we have reported previously ( Aguilar et al, 2014 ).…”

Dopamine and addiction: what have we learned from 40 years of research

“…It has been shown that a specific pathway that regulates the proportion of active DA neurons both in the SNc and the VTA is the ventral subiculum of the hippocampus (vSub)-NAc-VP-VTA/SNc pathway (Bortz and Grace 2018;Floresco et al 2001c;Floresco et al 2003). Two separate pathways from the NAc project to the VTA and the SNc: the NAc shell projects to the VTA and the NAc core projects to the SNc (Sesack and Grace 2010).…”