Afferent convergence to a shared population of interneuron AMPA receptors.

Precise alignment of pre- and postsynaptic elements optimizes the activation of glutamate receptors at excitatory synapses. Nonetheless, glutamate that diffuses out of the synaptic cleft can have actions at distant receptors, a mode of transmission called spillover. To uncover the extrasynaptic actions of glutamate, we localized AMPA receptors (AMPARs) mediating spillover transmission between climbing fibers and molecular layer interneurons in the cerebellar cortex.

Mesolimbic dopamine adapts the rate of learning from action.

Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions. Policy learning and value learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction; however, so far there has been little consideration of how direct policy learning might inform our understanding.

Dissociable contributions of phasic dopamine activity to reward and prediction.

Sensory cues that precede reward acquire predictive (expected value) and incentive (drive reward-seeking action) properties. Mesolimbic dopamine neurons' responses to sensory cues correlate with both expected value and reward-seeking action. This has led to the proposal that phasic dopamine responses may be sufficient to inform value-based decisions, elicit actions, and/or induce motivational states; however, causal tests are incomplete.

In Vivo Optogenetics with Stimulus Calibration.

Optogenetic reagents allow for depolarization and hyperpolarization of cells with light. This provides unprecedented spatial and temporal resolution to the control of neuronal activity both in vitro and in vivo. In the intact animal this requires strategies to deliver light deep into the highly scattering tissue of the brain.

Basal Ganglia Circuits for Action Specification.

Behavior is readily classified into patterns of movements with inferred common goals-actions. Goals may be discrete; movements are continuous. Through the careful study of isolated movements in laboratory settings, or via introspection, it has become clear that animals can exhibit exquisite graded specification to their movements.

Learning from Action: Reconsidering Movement Signaling in Midbrain Dopamine Neuron Activity.

Animals infer when and where a reward is available from experience with informative sensory stimuli and their own actions. In vertebrates, this is thought to depend upon the release of dopamine from midbrain dopaminergic neurons. Studies of the role of dopamine have focused almost exclusively on their encoding of informative sensory stimuli; however, many dopaminergic neurons are active just prior to movement initiation, even in the absence of sensory stimuli.

Expanding the Optogenetics Toolkit by Topological Inversion of Rhodopsins.

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed.

The timing of action determines reward prediction signals in identified midbrain dopamine neurons.

Animals adapt their behavior in response to informative sensory cues using multiple brain circuits. The activity of midbrain dopaminergic neurons is thought to convey a critical teaching signal: reward-prediction error. Although reward-prediction error signals are thought to be essential to learning, little is known about the dynamic changes in the activity of midbrain dopaminergic neurons as animals learn about novel sensory cues and appetitive rewards.

Non-synaptic signaling from cerebellar climbing fibers modulates Golgi cell activity.

Golgi cells are the principal inhibitory neurons at the input stage of the cerebellum, providing feedforward and feedback inhibition through mossy fiber and parallel fiber synapses. In vivo studies have shown that Golgi cell activity is regulated by climbing fiber stimulation, yet there is little functional or anatomical evidence for synapses between climbing fibers and Golgi cells. Here, we show that glutamate released from climbing fibers activates ionotropic and metabotropic receptors on Golgi cells through spillover-mediated transmission.

The contribution of extrasynaptic signaling to cerebellar information processing.

The diversity of synapses within the simple modular structure of the cerebellum has been crucial for study of the phasic extrasynaptic signaling by fast neurotransmitters collectively referred to as "spillover." Additionally, the accessibility of cerebellar components for in vivo recordings and their recruitment by simple behaviors or sensory stimuli has allowed for both direct and indirect demonstrations of the effects of transmitter spillover in the intact brain. The continued study of spillover in the cerebellum not only promotes our understanding of information transfer through cerebellar structures but also how extrasynaptic signaling may be regulated and interpreted throughout the CNS.

Increased expression of glutamate transporter GLT-1 in peritumoral tissue associated with prolonged survival and decreases in tumor growth in a rat model of experimental malignant glioma.

Object: Gliomas are known to release excessive amounts of glutamate, inducing glutamate excitotoxic cell death in the peritumoral region and allowing the tumor to grow and to expand. Glutamate transporter upregulation has been shown to be neuroprotective by removing extracellular glutamate in a number of preclinical animal models of neurodegenerative diseases, including amyotrophic lateral sclerosis and Parkinson disease as well as psychiatric disorders such as depression. The authors therefore hypothesized that the protective mechanism of glutamate transporter upregulation would be useful for the treatment of gliomas as well.

Spillover-mediated feedforward inhibition functionally segregates interneuron activity.

Neurotransmitter spillover represents a form of neural transmission not restricted to morphologically defined synaptic connections. Communication between climbing fibers (CFs) and molecular layer interneurons (MLIs) in the cerebellum is mediated exclusively by glutamate spillover. Here, we show how CF stimulation functionally segregates MLIs based on their location relative to glutamate release.

Human nasal olfactory epithelium as a dynamic marker for CNS therapy development.

Discovery of new central nervous system (CNS) acting therapeutics has been slowed down by the lack of useful applicable biomarkers of disease or drug action often due to inaccessibility of relevant human CNS tissue and cell types. In recent years, non-neuronal cells, such as astrocytes, have been reported to play a highly significant role in neurodegenerative diseases, CNS trauma, as well as psychiatric disease and have become a target for small molecule and biologic therapies. We report the development of a method for measuring pharmacodynamic changes induced by potential CNS therapeutics using nasal olfactory neural tissue biopsy.