![]() ![]() Transcriptomic and molecular studies have identified multiple distinct classes of dopaminergic neurons that exist within the same anatomic region ( Seroogy et al., 1988 Jayaraman et al., 1990 Rogers, 1992 Yamada et al., 1995 Liang et al., 1996 Numan and Seroogy, 1999 Neuhoff et al., 2002 Figlewicz et al., 2003 Korotkova et al., 2003 Cruz et al., 2004 Wang and Morales, 2008 Grieder et al., 2014 Poulin et al., 2014, 2018 Cork et al., 2015 La Manno et al., 2016 Pandit et al., 2016 Saunders et al., 2018 Tiklová et al., 2019). The methods and analysis employed provide a springboard for investigations of network topology in multiple deep brain structures and disorders.ĭopaminergic neurons are biochemically ( Poulin et al., 2014 Tiklová et al., 2019), structurally ( Margolis et al., 2006 Fu et al., 2012), and functionally heterogeneous ( Brown et al., 2009 Morales and Margolis, 2017 Saunders et al., 2018) and involved in a constellation of behaviors such as movement and value-based choice ( Schultz, 1986 Lerner et al., 2015 Beeler and Mourra, 2018 Beeler and Dreyer, 2019). SIGNIFICANCE STATEMENT In this work, we begin to untangle the differences in complex network properties between the substantia nigra pars compacta (SNC) and VTA, that may underlie differential sensitivity between regions. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Neuronal loss in the SNC increased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by decreasing network clustering in the VTA. We tested this hypothesis, in DAT-cre/loxP-GCaMP6f mice of either sex, when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC or VTA networks. Specifically, the frequency of hub-like neurons was significantly lower in SNC than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. Here, we used live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. Dopaminergic neurons of the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. ![]()
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