Medial septum activation produces opposite effects on dopamine neuron activity in the ventral tegmental area and substantia nigra in MAM vs. normal rats

Abstract

The medial septum (MS) differentially impacts midbrain dopamine (DA) neuron activity via the ventral hippocampus, a region implicated in DA-related disorders. However, whether MS regulation of ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is disrupted in a developmental disruption model of schizophrenia is unknown. Male Sprague-Dawley rats were exposed at gestational day 17 to methylazoxymethanol (MAM) or saline. As adults, NMDA (0.75 µg/0.2 µL) was infused into the MS, and either DA neuron activity in the VTA and SNc (7–9 anesthetized rats per group) or amphetamine-induced hyperlocomotion (AIH, 11-13 rats per group) was measured. MS activation produced a 58% increase in the number of spontaneously active DA neurons in VTA and a 37% decrease in SNc in saline rats. However, MS activation produced opposite effects on DA population activity in MAM rats, decreasing VTA DA activity by 51% and increasing SNc DA activity by 47%. MS activation also increased AIH by 113% in MAM rats, opposite of what is seen in intact rats. The effect in behavioral output may be due to disrupted GABAergic regulation of SNc as bicuculline infusion into vSub, which selectively prevented the MS activation-induced decrease in SNc DA activity in intact rats, prevented the increase in AIH and SNc DA activity in MAM rats. These findings demonstrate that the regulation of midbrain DA neurons by the MS is disrupted in this well-validated animal model, suggesting that it could be a potential locus for pharmacological intervention in disorders such as schizophrenia.

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).…”

“…These changes combined with the loss of cholinergic activation of a parallel set of GABAergic projections to vHipp pyramidal neurons that impact the substantia nigra (123,124) would increase vHipp drive of the VTA while increasing vHipp inhibition of the substantia nigra. Therefore, in contrast to the control condition, in the MAM rats the excitation of the substantia nigra combined with inhibition of the VTA would cause the subject to act before thinking, or causing impulsive behavior (133). Overall, the findings observed in MAM rats indicate that the medial septum-vHipp pathway as a potential target to reverse the hyperdopaminergic state in schizophrenia patients.…”

“…The concept is that activation of the VTA causes the subject to think about the action, while attenuation of the substantia nigra prevents action until after weighing options. 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).…”

The medial septum enhances reversal learning via opposing actions on ventral tegmental area and substantia nigra dopamine neurons

“…Proposed pathway from MS to midbrain and MS DREADD virus spread and expression. a Medial septum (MS) activation was shown previously to increase DA neuron population activity in the ventral tegmental area (VTA) and decrease it in the substantia nigra pars compacta (SNc) [23,24]. Both effects required activation of the ventral subiculum (vSub), as intra-vSub infusions of TTX prevented both the VTA increase and the SNc decrease in DA neuron population activity [23].…”

“…The MS has a well-established role in learning and memory processes [17][18][19][20], specifically in behaviors that require inhibition of prior learned information in order to learn a new rule [17,18,21] or prevention of attention to irrelevant stimuli [22]. Furthermore, we recently showed that MS activation potently regulates dopamine (DA) neuron population activity in both the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) [23,24], via a previously described circuit [25][26][27][28] (Fig. 1a) that includes the ventral subiculum of the hippocampus (vSub) and ventral pallidum [23].…”