A multi-compartment model for interneurons in the dorsal lateral geniculate nucleus

GABAergic interneurons (INs) in the dorsal lateral geniculate nucleus (dLGN) shape the information flow from retina to cortex, presumably by controlling the number of visually evoked spikes in geniculate thalamocortical (TC) neurons, and refining their receptive field. The INs exhibit a rich variety of firing patterns: Depolarizing current injections to the soma may induce tonic firing, periodic bursting or an initial burst followed by tonic spiking, sometimes with prominent spike-time adaptation. When released from hyperpolarization, some INs elicit rebound bursts, while others return more passively to the resting potential. A full mechanistic understanding that explains the function of the dLGN on the basis of neuronal morphology, physiology and circuitry is currently lacking. One way to approach such an understanding is by developing a detailed mathematical model of the involved cells and their interactions. Limitations of the previous models for the INs of the dLGN region prevent an accurate representation of the conceptual framework needed to understand the computational properties of this region. We here present a detailed compartmental model of INs using, for the first time, a morphological reconstruction and a set of active dendritic conductances constrained by experimental somatic recordings from INs under several different current-clamp conditions. The model makes a number of experimentally testable predictions about the role of specific mechanisms for the firing properties observed in these neurons. In addition to accounting for the significant features of all experimental traces, it quantitatively reproduces the experimental recordings of the action-potential- firing frequency as a function of injected current. We show how and why relative differences in conductance values, rather than differences in ion channel composition, could account for the distinct differences between the responses observed in two different neurons, suggesting that INs may be individually tuned to optimize network operation under different input conditions

Melanocortins and agouti-related protein modulate the excitability of two arcuate nucleus neuron populations by alteration of resting potassium conductances

The hypothalamic melanocortin system is crucial for the control of appetite and body weight. Two of the five melanocortin receptors, MC3R and MC4R are involved in hypothalamic control of energy homeostasis, with the MC4R having the major influence. It is generally thought that the main impact of the melanocortin system on hypothalamic circuits is external to the arcuate nucleus, and that any effect locally in the arcuate nucleus is inhibitory on proopiomelanocortin-expressing (POMC) neurons. In contrast, using current- and voltage-clamp recordings from identified neurons, we demonstrate that MC3R and MC4R agonists depolarize arcuate POMC neurons and a separate arcuate neuronal population identified by the rat insulin 2 promoter (RIPCre) transgene expression. Furthermore, the endogenous MC3R and MC4R antagonist, agouti-related protein (AgRP), hyperpolarizes POMC and RIPCre neurons in the absence of melanocortin agonist, consistent with inverse agonism at the MC4R. A decreased transient outward (I(A)) potassium conductance, and to a lesser extent the inward rectifier (K(IR)) conductance, underlies neuronal depolarization, whereas an increase in I(A) mediates AgRP-induced hyperpolarization. Accordingly, POMC and RIPCre neurons may be targets for peptide transmitters that are possibly released locally from AgRP-expressing and POMC neurons in the arcuate nucleus, adding further previously unappreciated complexity to the arcuate system

Short-term high-fat diet primes excitatory synapses for long-term depression in orexin neurons

Overconsumption of high-fat diets is one of the strongest contributing factors to the rise of obesity rates. Orexin neurons are known to be activated by palatable high-fat diet and mediate the activation of the mesolimbic reward pathway, resulting in further food intake. While short-term exposure to high-fat diet is known to induce synaptic plasticity within the mesolimbic pathway, it is unknown if such changes occur in orexin neurons. To investigate this, 3-week old male rats were fed a palatable high-fat western diet (WD) or control chow for 1 week and then in vitro patch clamp recording was performed. In the WD condition, an activity-dependent long-term depression (LTD) of excitatory synapses was observed in orexin neurons, but not in chow controls. This LTD was presynaptic and depended on postsynaptic metabotropic glutamate receptor 5 (mGluR5) and retrograde endocannabinoid signaling. WD also increased extracellular glutamate levels, suggesting that glutamate spillover and subsequent activation of perisynaptic mGluR5 may occur more readily in the WD condition. In support of this, pharmacological inhibition of glutamate uptake was sufficient to prime chow control synapses to undergo a presynaptic LTD. Interestingly, these WD effects are transient, as extracellular glutamate levels were similar to controls and LTD was no longer observed in orexin neurons after 4 weeks of WD. In summary, excitatory synapses to orexin neurons become amenable to LTD under palatable high-fat diet, which may represent a homeostatic mechanism to prevent overactivation of these neurons and to curtail high-fat diet consumption

Feedforward and recurrent inhibitory receptive fields of principal cells in the cat’s dorsal lateral geniculate nucleus

Principal cells in the dorsal lateral geniculate nucleus receive both feedforward and recurrent inhibition. Despite many years of study, the receptive field structure of these inhibitory mechanisms has not been determined. Here, we have used intracellular recordings in vivo to differentiate between the two types of inhibition and map their respective receptive fields. The feedforward inhibition of a principal cell originates from the same type of retinal ganglion cells as its excitation, while the recurrent inhibition is provided by both on- and off-centre cells. Both inhibitory effects are strongest at the centre of the excitatory receptive field. The diameter of the feedforward inhibitory field is two times larger, and the recurrent two to four times larger than the excitatory field centre. The inhibitory circuitry is similar for X and Y principal cells

Cholinergic Activation of M2 Receptors Leads to Context-Dependent Modulation of Feedforward Inhibition in the Visual Thalamus

The temporal dynamics of inhibition within a neural network is a crucial determinant of information processing. Here, the authors describe in the visual thalamus how neuromodulation governs the magnitude and time course of inhibition in an input-dependent way

NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice

BACKGROUND: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We thus generated two conditional knockout mouse models, Y2(lox/lox) and NPYCre/+;Y2(lox/lox), in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver carnitine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. CONCLUSIONS/SIGNIFICANCE: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone

Active Dendritic Conductances Dynamically Regulate GABA Release from Thalamic Interneurons

SummaryInhibitory interneurons in the dorsal lateral geniculate nucleus (dLGN) process visual information by precisely controlling spike timing and by refining the receptive fields of thalamocortical (TC) neurons. Previous studies indicate that dLGN interneurons inhibit TC neurons by releasing GABA from both axons and dendrites. However, the mechanisms controlling GABA release are poorly understood. Here, using simultaneous whole-cell recordings from interneurons and TC neurons and two-photon calcium imaging, we find that synchronous activation of multiple retinal ganglion cells (RGCs) triggers sodium spikes that propagate throughout interneuron axons and dendrites, and calcium spikes that invade dendrites but not axons. These distinct modes of interneuron firing can trigger both a rapid and a sustained component of inhibition onto TC neurons. Our studies suggest that active conductances make LGN interneurons flexible circuit-elements that can shift their spatial and temporal properties of GABA release in response to coincident activation of functionally related subsets of RGCs