Drug-evoked synaptic plasticity in the mesolimbic system reshapes circuit function and drives drug-adaptive behavior. Much research has focused on excitatory transmission in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). How drug-evoked synaptic plasticity of inhibitory transmission affects circuit adaptations remains unknown. We found that medium spiny neurons expressing dopamine (DA) receptor type 1 (D1R-MSNs) of the NAc project to the VTA, strongly preferring the GABA neurons of the VTA. Repeated in vivo exposure to cocaine evoked synaptic potentiation at this synapse, occluding homosynaptic inhibitory long-term potentiation. The activity of the VTA GABA neurons was thus reduced and DA neurons were disinhibited. Cocaine-evoked potentiation of GABA release from D1R-MSNs affected drug-adaptive behavior, which identifies these neurons as a promising target for novel addiction treatments.

How sleep influences brain plasticity is not known. In particular, why certain electroencephalographic (EEG) rhythms are linked to memory consolidation is poorly understood. Calcium activity in dendrites is known to be necessary for structural plasticity changes, but this has never been carefully examined during sleep. Here, we report that calcium activity in populations of neocortical dendrites is increased and synchronised during oscillations in the spindle range in naturally sleeping rodents. Remarkably, the same relationship is not found in cell bodies of the same neurons and throughout the cortical column. Spindles during sleep have been suggested to be important for brain development and plasticity. Our results provide evidence for a physiological link of spindles in the cortex specific to dendrites, the main site of synaptic plasticity.

BackgroundAddictive drugs have in common that they cause surges in dopamine (DA) concentration in the mesolimbic reward system and elicit synaptic plasticity in DA neurons of the ventral tegmental area (VTA). Cocaine for example drives insertion of GluA2-lacking AMPA receptors (AMPARs) at glutamatergic synapes in DA neurons. However it remains elusive which molecular target of cocaine drives such AMPAR redistribution and whether other addictive drugs (morphine and nicotine) cause similar changes through their effects on the mesolimbic DA system.Methodology / Principal FindingsWe used in vitro electrophysiological techniques in wild-type and transgenic mice to observe the modulation of excitatory inputs onto DA neurons by addictive drugs. To observe AMPAR redistribution, post-embedding immunohistochemistry for GluA2 AMPAR subunit was combined with electron microscopy. We also used a double-floxed AAV virus expressing channelrhodopsin together with a DAT Cre mouse line to selectively express ChR2 in VTA DA neurons. We find that in mice where the effect of cocaine on the dopamine transporter (DAT) is specifically blocked, AMPAR redistribution was absent following administration of the drug. Furthermore, addictive drugs known to increase dopamine levels cause a similar AMPAR redistribution. Finally, activating DA VTA neurons optogenetically is sufficient to drive insertion of GluA2-lacking AMPARs, mimicking the changes observed after a single injection of morphine, nicotine or cocaine.Conclusions / SignificanceWe propose the mesolimbic dopamine system as a point of convergence at which addictive drugs can alter neural circuits. We also show that direct activation of DA neurons is sufficient to drive AMPAR redistribution, which may be a mechanism associated with early steps of non-substance related addictions.

Declarative memory formation is believed to rely on interactions between the medial temporal lobe (MTL) and neocortex. However, the distributed nature of neocortical networks has hindered investigation on cellular targets and mechanisms of memory formation in the neocortex. The six-layered mammalian neocortex has an anatomical organization in which top-down inputs converge on its outermost layer, layer 1 (L1). We investigated this organization to examine how layer-specific MTL inputs modulate neocortical activity and memory formation. To this end, we first adapted a cortical-and hippocampal-dependent learning paradigm, in which animals were trained to associate direct cortical microstimulation and reward, and characterized learning behavior of rats and mice during this task. We next showed that neurons in the deep layers of the perirhinal cortex not only provide monosynaptic inputs to L1 of the primary somatosensory cortex (S1), where microstimulation was presented, but also actively reflect the behavioral outcome. Chemogenetic suppression of perirhinal inputs to L1 of S1 disrupted early memory formation but did not affect animals' performance after learning. The learning was followed by an emergence of a distinct subpopulation of layer 5 (L5) pyramidal neurons (~10%) characterized by high-frequency burst firing, which could be reduced by blocking perirhinal inputs to L1. Interestingly, similar proportion of apical dendrites (~10%) of L5 pyramidal neurons also displayed significantly enhanced calcium (Ca 2+ ) activity during memory retrieval in expert animals. Importantly, disrupting dendritic Ca 2+ activity impaired learning, suggesting that apical dendrites of L5 pyramidal neurons have a critical role in neocortical memory formation. Taken together, these results suggest that MTL inputs control learning via a perirhinal-mediated gating process in L1, manifested by elevated dendritic Ca 2+ activity and burst firing in L5 pyramidal neurons. The present study provides insights into cellular mechanisms of learning and memory representations in the neocortex. Zusammenfassung SHIN (2020) ___________________________________________________________________________ 2 Zusammenfassung Es wird angenommen, dass deklarative Gedächtnisbildung auf Wechselwirkungen zwischen dem medialen Temporallappens (MTL) und dem Neokortex beruht. Die Untersuchung der zellulären Ziele und Mechanismen von Gedächtnisbildung im Neokortex wird erschwert durch die über den Kortex verteilte Struktur neokortikaler Netzwerke. Der in sechs Schichten gegliederte Neokortex von Säugetieren besitzt eine anatomische Organisation, in der Top-Down-Inputs inseiner äußersten Schicht, Schicht 1 (L1), konvergieren. Wir haben diese Organisation untersucht, um zu verstehen, wie schichtspezifische MTL-Inputs die neokortikale Aktivität und die Gedächtnisbildung modulieren. Zu diesem Zweck haben wir ein Kortex-und Hippocampus-abhängiges Lernparadigma angepasst, in dem Tiere darauf trainiert wurden, direkte kortikale Mikrostimulation und Belohnung zu assoziieren, und...

The differential regulation of the two major N-methyl-D-aspartate receptor (NMDAR) subunits GluN2A and GluN2B during development in forebrain pyramidal cells has been thoroughly investigated. In contrast, much less is known about the role of GluN2D, which is expressed at low levels and is downregulated following the second postnatal week. However, it appears that few cells, presumably interneurons, continue to express GluN2D also in juvenile mice. To investigate which hippocampal cell types express this subunit, we generated transgenic mice with EGFP-tagged GluN2D receptors. The expression of the transgene was confined to hippocampal interneurons, most of which were parvalbumin- and/or somatostatin-positive. Electrophysiological and morphological analyses showed that GluN2D was present mainly in fast spiking basket and axo-axonic cells. Based on pharmacological evidence and electrophysiological analysis of GluN2D knockout mice, we conclude that GluN2D-containing NMDARs mediate synaptic currents in hippocampal interneurons of young and juvenile mice and in CA1 pyramidal neurons of newborn mice.