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

David M Bortz,Anthony A Grace

doi:10.1038/s41537-018-0059-3

David M Bortz, Anthony A Grace

Open Access

https://doi.org/10.1038/s41537-018-0059-3

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Journal: NPJ schizophrenia	Publication Date: Sep 3, 2018
Citations: 12	License type: open-access

Affiliation: University of Pittsburgh

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.

Highlights

Dependent measures included DA population activity, neuron firing rate, percentage of spikes occurring in bursts, and total distance traveled
Significance is defined as P < 0.05 (IBM SPSS Statistics 22)
The medial septum (MS) has been shown previously to regulate amphetamine-induced hyperlocomotion (AIH) and DA population activity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of intact rats via a multisynaptic pathway (Supplementary Figure 2) that projects through the ventral hippocampus and ventral pallidum.[13] The ability of this pathway to regulate DA activity has been shown by direct modulation of the ventral hippocampus,[30] nucleus accumbens,[30,31] and ventral pallidum,[13,21,32] providing evidence for the specific circuit that is likely to mediate the effects shown here

Summary

Introduction

Schizophrenia is a devastating disorder characterized by dopamine (DA) dysregulation in human patients[1,2] and rodent models.[3,4,5] This dysregulation is thought to be caused by pathology within the upstream circuits that control DA activity, such as the hippocampus[6,7,8,9], rather than in the DA system itself.[5,10,11,12] As such, characterizing the circuits that regulate DA transmission in intact animals and animal models remains a high priority.One brain region that is a potent regulator of DA neuron activity in both the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) is the medial septum (MS).[13]. For a DA neuron to burst fire, the neuron must be depolarized and spontaneously active; if it is hyperpolarized the magnesium block of the NMDA channel prevents NMDA-driven burst firing.[21,22,23] by regulating the number of neurons that are spontaneously active, the MS to midbrain pathway controls the “gain” of the burst firing “signal”, effectively setting a “context” for behaviorally relevant DA transmission from both the VTA and SNc.[13,24]

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