Electroresponsive properties of rat central medial thalamic neurons

The central medial thalamic (CMT) nucleus is a poorly known component of the middle thalamic complex that relays nociceptive inputs to the basolateral amygdala and cingulate cortex and plays a critical role in the control of awareness. The present study was undertaken to characterize the electroresponsive properties of CMT neurons. Similar to relay neurons found throughout the dorsal thalamus, CMT cells assumed tonic or burst-firing modes, depending on their membrane potentials (Vm). However, they showed little evidence of the hyperpolarization-activated mixed cationic conductance (IH)-mediated inward rectification usually displayed by dorsal thalamic relay cells at hyperpolarized Vm. Two subtypes of CMT neurons were identified when comparing their responses with depolarization applied from negative potentials. Some cells generated a low-threshold spike burst followed by tonic firing, whereas others remained silent after the initial burst, irrespective of the amount of depolarizing current injected. Equal proportions of the two cell types were found among neurons retrogradely labeled from the basolateral amygdala. Their morphological properties were heterogeneous but distinct from the classical bushy relay cell type that prevails in most of the dorsal thalamus. We propose that the marginal influence of IH in CMT relative to other dorsal thalamic nuclei has significant network-level consequences. Because IH promotes the genesis of highly coherent delta oscillations in thalamocortical networks during sleep, these oscillations may be weaker or less coherent in CMT. Consequently, delta oscillations would be more easily disrupted by peripheral inputs, providing a potential mechanism for the reported role of CMT in eliciting arousal from sleep or anesthesia.

Visual signal processing in the macaque lateral geniculate nucleus

Comparisons of S- or prepotential activity, thought to derive from a retinal ganglion cell afferent, with the activity of relay cells of the lateral geniculate nucleus (LGN) have sometimes implied a loss, or leak, of visual information. The idea of the “leaky” relay cell is reconsidered in the present analysis of prepotential firing and LGN responses of color-opponent cells of the macaque LGN to stimuli varying in size, relative luminance, and spectral distribution. Above a threshold prepotential spike frequency, called the signal transfer threshold (STT), there is a range of more than 2 log units of test field luminance that has a 1:1 relationship between prepotential- and LGN-cell firing rates. Consequently, above this threshold, the LGN cell response can be viewed as an extension of prepotential firing (a “nonleaky relay cell”). The STT level decreased when the size of the stimulus increased beyond the classical receptive field center, indicating that the LGN cell is influenced by factors other than the prepotential input. For opponent ON cells, both the excitatory and the inhibitory response decreased similarly when the test field size increased beyond the center of the receptive field. These findings have consequences for the modeling of LGN cell responses and transmission of visual information, particularly for small fields. For instance, for LGN ON cells, information in the prepotential intensity–response curve for firing rates below the STT is left to be discriminated by OFF cells. Consequently, for a given light adaptation, the STT improves the separation of the response range of retinal ganglion cells into “complementary” ON and OFF pathways.

Neuromodulation by GABA Converts a Relay Into a Coincidence Detector

Modulation of synaptic strength by γ-aminobutyric acid receptors (GABARs) is a common feature in sensory pathways that contain relay cell types. However, the functional impact of these receptors on information processing is not clear. We considered this issue at bushy cells (BCs) in the cochlear nucleus, which relay auditory nerve (AN) activity to higher centers. BCs express GABAARs, and synaptic inputs to BCs express GABABRs. We tested the effects of GABAR activation on the relaying of AN activity using patch-clamp recordings in mature mouse brain slices at 34°C. GABA affected BC firing in response to trains of AN activity at concentrations as low as 10 μM. GABAARs reduced firing primarily late in high-frequency trains, whereas GABABRs reduced firing early and in low-frequency trains. BC firing was significantly restored when two converging AN inputs were activated simultaneously, with maximal effect over a window of <0.5 ms. Thus GABA could adjust the function of BCs, to suppress the relaying of individual inputs and require coincident activity of multiple inputs.

Populations of Tightly Coupled Neurons: The RGC/LGN System

A mathematical model, of general character for the dynamic description of coupled neural oscillators is presented. The population approach that is employed applies equally to coupled cells as to populations of such coupled cells. The formulation includes stochasticity and preserves details of precisely firing neurons. Based on the generally accepted view of cortical wiring, this formulation is applied to the retinal ganglion cell (RGC)/lateral geniculate nucleus (LGN) relay cell system, of the early mammalian visual system. The smallness of quantal voltage jumps at the retinal level permits a Fokker-Planck approximation for the RGC contribution; however, the LGN description requires the use of finite jumps, which for fast synaptic dynamics appears as finite jumps in the membrane potential. Analyses of equilibrium spiking behavior for both the deterministic and stochastic cases are presented. Green's function methods form the basis for the asymptotic and exact results that are presented. This determines the spiking ratio (i.e., the number of RGC arrivals per LGN spike), which is the reciprocal of the transfer ratio, under wide circumstances. Criteria for spiking regimes, in terms of the relatively few parameters of the model, are presented. Under reasonable hypotheses, it is shown that the transfer ratio is ≤1/2, in the absence of input from other areas. Thus, the model suggests that the LGN/RGC system may be a relatively unsophisticated spike editor. In the absence of other input, the system is designed to fire an LGN spike only when two or more RGC spikes appear in a relatively short time. Transfer ratios that briefly exceed 1/2 (but are less than 1) have been recorded in the laboratory. Inclusion of brain stem input has been shown to provide a signal that elevates the transfer ratio (Ozaki & Kaplan, 2006). A model that includes this contribution is also presented.

Thalamocortical Relay Fidelity Varies Across Subthalamic Nucleus Deep Brain Stimulation Protocols in a Data-Driven Computational Model

The therapeutic effectiveness of deep brain stimulation (DBS) of the subthalamic nucleus (STN) may arise through its effects on inhibitory basal ganglia outputs, including those from the internal segment of the globus pallidus (GPi). Changes in GPi activity will impact its thalamic targets, representing a possible pathway for STN-DBS to modulate basal ganglia-thalamocortical processing. To study the effect of STN-DBS on thalamic activity, we examined thalamocortical (TC) relay cell responses to an excitatory input train under a variety of inhibitory signals, using a computational model. The inhibitory signals were obtained from single-unit GPi recordings from normal monkeys and from monkeys rendered parkinsonian through arterial 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine injection. The parkinsonian GPi data were collected in the absence of STN-DBS, under sub-therapeutic STN-DBS, and under therapeutic STN-DBS. Our simulations show that inhibition from parkinsonian GPi activity recorded without DBS-compromised TC relay of excitatory inputs compared with the normal case, whereas TC relay fidelity improved significantly under inhibition from therapeutic, but not sub-therapeutic, STN-DBS GPi activity. In a heterogeneous model TC cell population, response failures to the same input occurred across multiple TC cells significantly more often without DBS than in the therapeutic DBS case and in the normal case. Inhibitory signals preceding successful TC relay were relatively constant, whereas those before failures changed more rapidly. Computationally generated inhibitory inputs yielded similar effects on TC relay. These results support the hypothesis that STN-DBS alters parkinsonian GPi activity in a way that may improve TC relay fidelity.

Mapping of the Functional Interconnections Between Thalamic Reticular Neurons Using Photostimulation

The thalamic reticular nucleus is strategically located in the axonal pathways between thalamus and cortex, and reticular cells exert strong, topographic inhibition on thalamic relay cells. Although evidence exists that reticular neurons are interconnected through conventional and electrical synapses, the spatial extent and relative strength of these synapses are unclear. To address these issues, we used uncaging of glutamate by laser-scanning photostimulation to provide precisely localized and consistent activation of reticular cell bodies and dendrites in an in vitro slice preparation from the rat as a means to study reticulo-reticular connections. Among the 47 recorded reticular neurons, 29 (62%) received GABAergic axodendritic input from an area immediately surrounding each of the recorded cell bodies, and 8 (17%) responded with depolarizing spikelets, suggesting inputs through electrical synapses. We also found that TTX completely blocked all evoked IPSCs, implying that any dendrodendritic synapses between reticular cells either are relatively weak, have no nearby glutamatergic receptors, or are dependent on back-propagation of action potentials. Finally, we showed that the GABAergic connections between reticular cells are weaker than those from reticular cells to relay cells. Our results suggest that the GABAergic axodendritic synapse is the dominant form of reticulo-reticular connectivity, and because they are much weaker than the reticulo-relay cell synapses, their functional purpose may be to regulate the spatial extent of the reticular inhibition on relay cells.

Distinct Roles of PI(3,4,5)P3 during Chemoattractant Signaling in Dictyostelium: A Quantitative In Vivo Analysis by Inhibition of PI3-Kinase

The role of PI(3,4,5)P3 in Dictyostelium signal transduction and chemotaxis was investigated using the PI3-kinase inhibitor LY294002 and pi3k-null cells. The increase of PI(3,4,5)P3 levels after stimulation with the chemoattractant cAMP was blocked >95% by 60 μM LY294002 with half-maximal effect at 5 μM. This correlated well with the inhibition of the membrane translocation of the PH-domain protein, PHcracGFP. LY294002 did not reduce cAMP-mediated cGMP production, but significantly reduced the cAMP response up to 75% in wild type and completely in pi3k-null cells. LY294002-treated cells were round, not elongated as control cells. Interestingly, cAMP induced a time and dose-dependent recovery of cell elongation. These elongated LY294002-treated wild-type and pi3k-null cells exhibited chemotactic orientation toward cAMP that is statistically identical to chemotactic orientation of control cells. In control cells, PHcrac-GFP and F-actin colocalize upon cAMP stimulation. However, inhibition of PI3-kinases does not affect the first phase of the actin polymerization at a wide range of chemoattractant concentrations. Our data show that severe inhibition of cAMP-mediated PI(3,4,5)P3 accumulation leads to inhibition of cAMP relay, cell elongation and cell aggregation, but has no detectable effect on chemotactic orientation, provided that cAMP had sufficient time to induce cell elongation.