Cholinergic neurotransmission affects decision-making, notably through the modulation of perceptual processing in the cortex. In addition, acetylcholine acts on value-based decisions through as yet unknown mechanisms. We found that nicotinic acetylcholine receptors (nAChRs) expressed in the ventral tegmental area (VTA) are involved in the translation of expected uncertainty into motivational value. We developed a multi-armed bandit task for mice with three locations, each associated with a different reward probability. We found that mice lacking the nAChR β2 subunit showed less uncertainty-seeking than their wild-type counterparts. Using model-based analysis, we found that reward uncertainty motivated wild-type mice, but not mice lacking the nAChR β2 subunit. Selective re-expression of the β2 subunit in the VTA was sufficient to restore spontaneous bursting activity in dopamine neurons and uncertainty-seeking. Our results reveal an unanticipated role for subcortical nAChRs in motivation induced by expected uncertainty and provide a parsimonious account for a wealth of behaviors related to nAChRs in the VTA expressing the β2 subunit.

No abstract

Individuality is a striking feature of animal behavior. Individual animals differ in traits and preferences which shape their interactions and their prospects for survival. However, the mechanisms underlying behavioral individuation are poorly understood and are generally considered to be genetic-based. Here, we devised a large environment, Souris City, in which mice live continuously in large groups. We observed the emergence of individual differences in social behavior, activity levels, and cognitive traits, even though the animals had low genetic diversity (inbred C57BL/6J strain). We further show that the phenotypic divergence in individual behaviors was mirrored by developing differences in midbrain dopamine neuron firing properties. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animal’s traits and its dopamine firing pattern. Individuality can rapidly change upon social challenges, and does not just depend on the genetic status or the accumulation of small differences throughout development.

Dopamine (DA) neurons of the ventral tegmental area (VTA) integrate cholinergic inputs to regulate key functions such as motivation and goal-directed behaviors. Yet the temporal dynamic range and mechanism of action of acetylcholine (ACh) on the modulation of VTA circuits and reward-related behaviors are not known. Here, we used a chemical-genetic approach for rapid and precise optical manipulation of nicotinic neurotransmission in VTA neurons in living mice. We provide direct evidence that the ACh tone fine-tunes the firing properties of VTA DA neurons through β2-containing (β2*) nicotinic ACh receptors (nAChRs). Furthermore, locally photo-antagonizing these receptors in the VTA was sufficient to reversibly switch nicotine reinforcement on and off. By enabling control of nicotinic transmission in targeted brain circuits, this technology will help unravel the various physiological functions of nAChRs and may assist in the design of novel therapies relevant to neuropsychiatric disorders.

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with KCNJ11 and ABCC8 subunits, which we show are functionally expressed in most neocortical neuronal types. We also demonstrate the ability of cortical neurons to take-up and metabolize lactate. We further reveal that ATP is produced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis. Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate, and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function.

Homeostatic intrinsic plasticity (HIP) is a ubiquitous cellular mechanism regulating neuronal activity, cardinal for the proper functioning of nervous systems. In invertebrates, HIP is critical for orchestrating stereotyped activity patterns. The functional impact of HIP remains more obscure in vertebrate networks, where higher order cognitive processes rely on complex neural dynamics. The hypothesis has emerged that HIP might control the complexity of activity dynamics in recurrent networks, with important computational consequences. However, conflicting results about the causal relationships between cellular HIP, network dynamics, and computational performance have arisen from machinelearning studies. Here, we assess how cellular HIP effects translate into collective dynamics and computational properties in biological recurrent networks. We develop a realistic multiscale model including a generic HIP rule regulating the neuronal threshold with actual molecular signaling pathways kinetics, Dale's principle, sparse connectivity, synaptic balance, and Hebbian synaptic plasticity (SP). Dynamic mean-field analysis and simulations unravel that HIP sets a working point at which inputs are transduced by large derivative ranges of the transfer function. This cellular mechanism ensures increased network dynamics complexity, robust balance with SP at the edge of chaos, and improved input separability. Although critically dependent upon balanced excitatory and inhibitory drives, these effects display striking robustness to changes in network architecture, learning rates, and input features. Thus, the mechanism we unveil might represent a ubiquitous cellular basis for complex dynamics in neural networks. Understanding this robustness is an important challenge to unraveling principles underlying self-organization around criticality in biological recurrent neural networks.

Although the prefrontal cortex and basal ganglia are functionally interconnected by parallel loops, cellular substrates underlying their interaction remain poorly understood. One novel approach for addressing this issue is microfluidics, a methodology which recapitulates several intrinsic and synaptic properties of cortico-subcortical networks. We developed a microfluidic device where cortical neurons projected onto striatal neurons in a separate compartment. We exploited real-time (low-resolution/high-output) calcium imaging to register network dynamics and characterize the response to glutamatergic and dopaminergic agents. Reconstructed cortico-striatal networks revealed the progressive appearance of cortical VGLUT1 clusters on striatal dendrites, correlating with the emergence of spontaneous and synchronous glutamatergic responses of striatal neurons to concurrent cortical stimulation. Striatal exposure to the NMDA receptor GluN2A subunit antagonist TCN201 did not affect network rhythm, whereas the GluN2B subunit antagonist RO256981 significantly decreased striatal activity. Dopamine application or the D2/D3 receptor agonist, quinpirole, decreased cortico-striatal synchrony whereas the D1 receptor agonist, SKF38393, was ineffective. These data show that cortico-striatal networks reconstructed in a microfluidic environment are synchronized and present characteristics close to those of their in situ counterparts. They should prove instructive for deciphering the molecular substrates of CNS disorders and evaluating the actions of novel therapeutic agents.

No abstract