Methamphetamine regulation of activity and topology of ventral midbrain networks

Abstract

The ventral midbrain supports a variety of functions through the heterogeneity of neurons. Dopaminergic and GABA neurons within this region are particularly susceptible targets of amphetamine-class psychostimulants such as methamphetamine. While this has been evidenced through single-neuron methods, it remains unclear whether and to what extent the local neuronal network is affected and if so, by which mechanisms. Both GABAergic and dopaminergic neurons were heavily featured within the primary ventral midbrain network model system. Using spontaneous calcium activity, our data suggest methamphetamine decreased total network output via a D2 receptor-dependent manner. Over culture duration, functional connectivity between neurons decreased significantly but was unaffected by methamphetamine. However, across culture duration, exposure to methamphetamine significantly altered changes in network assortativity. Here we have established primary ventral midbrain networks culture as a viable model system that reveals specific changes in network activity, connectivity, and topology modulation by methamphetamine. This network culture system enables control over the type and number of neurons that comprise a network and facilitates detection of emergent properties that arise from the specific organization. Thus, the multidimensional properties of methamphetamine can be unraveled, leading to a better understanding of its impact on the local network structure and function.

Novel insights in the pathophysiology of α-synuclein dysregulation on D2 receptor activity contributing to the vulnerability of dopamine neurons

“…Both firing activity and calcium dynamics in dopamine neurons are tightly regulated by the activity of the D2 autoinhibitory receptors [33][34][35][36][37] . Therefore, we asked whether α-syn-Although live cell calcium imaging provides a proxy for dopamine neuronal activity 50 , calcium imaging does not reveal changes in firing activity at the resolution of electrophysiological recordings. Therefore, as a complementary approach, we utilized whole-cell current clamp recordings to compare the spontaneous firing activity of naive and α-syn overexpressing dopaminergic neurons following quinpirole administration.…”

“…Primary Neuronal Culture: Primary culture was prepared as previously described, with small distinctions 50 . Briefly, acutely dissociated mouse midbrains from 0-2-day old male and female pups were isolated and incubated in dissociation medium at 35-37 °C under continuous oxygenation for 60-90 min.…”

Dopamine transporter is a master regulator of dopaminergic neural network connectivity

“…Functional networks emerge from local interactions between neurons 46,47,49 . In dopaminergic networks, dopamine neurons have the machinery to directly interact through both synaptic and non-synaptic signaling 65,91,130 . However these studies do not account for dopaminergic network properties and dynamics, and how they differ by brain region.…”

“…Network assortativity, an evaluative measurement of preferential connectivity to neurons with similar or dissimilar connection strength 65,108,149,150 . Assortativity (r) was calculated as defined by:…”

Allosterically Potentiated α7 Nicotinic Acetylcholine Receptors: Reduced Calcium Permeability and Current-Independent Control of Intracellular Calcium

“…Videos were acquired with a 1-minute baseline for normalization. As previously published (Goodwin et al, 2009;Miller et al, 2019), Calcium signals were normalized to median fluorescence prior to drug administration using the function F(t) = ΔF/F0 where F0 is the median fluorescence prior to drug administration.…”