Mechanisms of gain control by voltage-gated channels in intrinsically-firing neurons.

This is the final published version. It first appeared at http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0115431.Gain modulation is a key feature of neural information processing, but underlying mechanisms remain unclear. In single neurons, gain can be measured as the slope of the current-frequency (input-output) relationship over any given range of inputs. While much work has focused on the control of basal firing rates and spike rate adaptation, gain control has been relatively unstudied. Of the limited studies on gain control, some have examined the roles of synaptic noise and passive somatic currents, but the roles of voltage-gated channels present ubiquitously in neurons have been less explored. Here, we systematically examined the relationship between gain and voltage-gated ion channels in a conductance-based, tonically-active, model neuron. Changes in expression (conductance density) of voltage-gated channels increased (Ca2+ channel), reduced (K+ channels), or produced little effect (h-type channel) on gain. We found that the gain-controlling ability of channels increased exponentially with the steepness of their activation within the dynamic voltage window (voltage range associated with firing). For depolarization-activated channels, this produced a greater channel current per action potential at higher firing rates. This allowed these channels to modulate gain by contributing to firing preferentially at states of higher excitation. A finer analysis of the current-voltage relationship during tonic firing identified narrow voltage windows at which the gain-modulating channels exerted their effects. As a proof of concept, we show that h-type channels can be tuned to modulate gain by changing the steepness of their activation within the dynamic voltage window. These results show how the impact of an ion channel on gain can be predicted from the relationship between channel kinetics and the membrane potential during firing. This is potentially relevant to understanding input-output scaling in a wide class of neurons found throughout the brain and other nervous systems.This work was supported by the Wellcome Trust- and GSK-funded TMAT programme (085686/ Z/08/C, AXP), the University of Cambridge MB/PhD Programme (AXP), the European Research Council (FP7 starting grant to DB) and the UK Medical Research Council (DB, ref: MC\_UP\_1202/2). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Rationality, preferences, and emotions with biological constraints: it all starts from our senses

Is the role of our sensory systems to represent the physical world as accurately as possible? If so, are our preferences and emotions, often deemed irrational, decoupled from these 'ground-truth' sensory experiences? We show why the answer to both questions is 'no'. Brain function is metabolically costly, and the brain loses some fraction of the information that it encodes and transmits. Therefore, if brains maximize objective functions that increase the fitness of their species, they should adapt to the objective-maximizing rules of the environment at the earliest stages of sensory processing. Consequently, observed 'irrationalities', preferences, and emotions stem from the necessity for our early sensory systems to adapt and process information while considering the metabolic costs and internal states of the organism

Metabolism-Independent Sugar Sensing in Central Orexin Neurons

OBJECTIVE— Glucose sensing by specialized neurons of the hypothalamus is vital for normal energy balance. In many glucose-activated neurons, glucose metabolism is considered a critical step in glucose sensing, but whether glucose-inhibited neurons follow the same strategy is unclear. Orexin/hypocretin neurons of the lateral hypothalamus are widely projecting glucose-inhibited cells essential for normal cognitive arousal and feeding behavior. Here, we used different sugars, energy metabolites, and pharmacological tools to explore the glucose-sensing strategy of orexin cells

Awake dynamics and brain-wide direct inputs of hypothalamic MCH and orexin networks

Acknowledgments: Work funded by a Marie Curie Intra-European Fellowship FP7-PEOPLE-2009-IEF Project number 255559 to J.A.G.). The authors declare no conflicts of interest.Peer reviewedPublisher PD

Stimulation of VTA dopamine inputs to LH upregulates orexin neuronal activity in a DRD2-dependent manner

Dopamine and orexins (hypocretins) play important roles in regulating reward-seeking behaviors. It is known that hypothalamic orexinergic neurons project to dopamine neurons in the ventral tegmental area (VTA), where they can stimulate dopaminergic neuronal activity. Although there are reciprocal connections between dopaminergic and orexinergic systems, whether and how dopamine regulates the activity of orexin neurons is currently not known. Here we implemented an opto-Pavlovian task in which mice learn to associate a sensory cue with optogenetic dopamine neuron stimulation to investigate the relationship between dopamine release and orexin neuron activity in the LH. We found that dopamine release can be evoked in LH upon optogenetic stimulation of VTA dopamine neurons, and is also naturally evoked by cue presentation after opto-Pavlovian learning. Furthermore, orexin neuron activity could also be upregulated by local stimulation of dopaminergic terminals in the LH in a way that is partially dependent on dopamine D2 receptors (DRD2). Our results reveal previously unknown orexinergic coding of reward expectation and unveil an orexin-regulatory axis mediated by local dopamine inputs in the LH. Optical VTA DA neuron stimulation is sufficient to elicit a Pavlovian-like dopamine transient in the NAc Dopamine in the LH encodes both negative and positive reward prediction errors Dopamine in the LH positively modulates orexin neuronal activity locally in a D2R dependent wa

Inhibitory Interplay between Orexin Neurons and Eating

We thank Drs. Cornelia Scho¨ ne, Rui Costa, and Guohong Cui for their assistance with fiber photometry. This work was funded by The Francis Crick Institute, which receives its core funding from Cancer Research UK, the UK Medical Research Council, and the Wellcome Trust. L.F. is supported by the MRC and the Wellcome Trust.Peer reviewedPublisher PD

5-HT obesity medication efficacy via POMC activation is maintained during aging

Peer reviewedPublisher PD

5-HT2C Receptor Agonist Anorectic Efficacy Potentiated by 5-HT1B Receptor Agonist Coapplication: An Effect Mediated via Increased Proportion of Pro-Opiomelanocortin Neurons Activated

An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (~25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists alone. These data indicate a functional heterogeneity ofARCPOMCneurons by revealing distinct subpopulations of POMC cells activated by 5-HT2CRs and disinhibited by 5-HT1BRs. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment. © 2013 the authors

Role of spontaneous and sensory orexin network dynamics in rapid locomotion initiation.

Appropriate motor control is critical for normal life, and requires hypothalamic hypocretin/orexin neurons (HONs). HONs are slowly regulated by nutrients, but also display rapid (subsecond) activity fluctuations in vivo. The necessity of these activity bursts for sensorimotor control and their roles in specific phases of movement are unknown. Here we show that temporally-restricted optosilencing of spontaneous or sensory-evoked HON bursts disrupts locomotion initiation, but does not affect ongoing locomotion. Conversely, HON optostimulation initiates locomotion with subsecond delays in a frequency-dependent manner. Using 2-photon volumetric imaging of activity of >300 HONs during sensory stimulation and self-initiated locomotion, we identify several locomotion-related HON subtypes, which distinctly predict the probability of imminent locomotion initiation, display distinct sensory responses, and are differentially modulated by food deprivation. By causally linking HON bursts to locomotion initiation, these findings reveal the sensorimotor importance of rapid spontaneous and evoked fluctuations in HON ensemble activity

Orexin neurons track temporal features of blood glucose in behaving mice

Does the brain track how fast our blood glucose is changing? Knowing such a rate of change would enable the prediction of an upcoming state and a timelier response to this new state. Hypothalamic arousal-orchestrating hypocretin/orexin neurons (HONs) have been proposed to be glucose sensors, yet whether they track glucose concentration (proportional tracking) or rate of change (derivative tracking) is unknown. Using simultaneous recordings of HONs and blood glucose in behaving male mice, we found that maximal HON responses occur in considerable temporal anticipation (minutes) of glucose peaks due to derivative tracking. Analysis of >900 individual HONs revealed glucose tracking in most HONs (98%), with derivative and proportional trackers working in parallel, and many (65%) HONs multiplexed glucose and locomotion information. Finally, we found that HON activity is important for glucose-evoked locomotor suppression. These findings reveal a temporal dimension of brain glucose sensing and link neurobiological and algorithmic views of blood glucose perception in the brain's arousal orchestrators