Intrinsic properties and neuropharmacology of midline paraventricular thalamic nucleus neurons

Abstract

Neurons in the midline and intralaminar thalamic nuclei are components of an interconnected brainstem, limbic and prefrontal cortex neural network that is engaged during arousal, vigilance, motivated and addictive behaviors, and stress. To better understand the cellular mechanisms underlying these functions, here we review some of the recently characterized electrophysiological and neuropharmacological properties of neurons in the paraventricular thalamic nucleus (PVT), derived from whole cell patch clamp recordings in acute rat brain slice preparations. PVT neurons display firing patterns and ionic conductances (IT and IH) that exhibit significant diurnal change. Their resting membrane potential (RMP) is maintained by various ionic conductances that include inward rectifier (Kir), hyperpolarization-activated nonselective cation (HCN) and TWIK-related acid sensitive (TASK) K(+) channels. Firing patterns are regulated by high voltage-activated (HVA) and low voltage-activated (LVA) Ca(2+) conductances. Moreover, transient receptor potential (TRP)-like nonselective cation channels together with Ca(2+)- and Na(+)-activated K(+) conductances (KCa; KNa) contribute to unique slow afterhyperpolarizing potentials (sAHPs) that are generally not detectable in lateral thalamic or reticular thalamic nucleus neurons. The excitability of PVT neurons is also modulated by activation of neurotransmitter receptors associated with afferent pathways to PVT and other thalamic midline nuclei. We report on receptor-mediated actions of GABA, glutamate, monoamines and several neuropeptides: arginine vasopressin, gastrin-releasing peptide, thyrotropin releasing hormone and the orexins (hypocretins). This review represents an initial survey of intrinsic and transmitter-sensitive ionic conductances that are deemed to be unique to this population of midline thalamic neurons, information that is fundamental to an appreciation of the role these thalamic neurons may play in normal central nervous system (CNS) physiology and in CNS disorders that involve the dorsomedial thalamus.

Keywords: burst firing; diurnal and seasonal changes; electrophysiology; midline thalamic nuclei; peptides.

Figure 1

PVT neurons express diurnal changes. A schematic illustrating the differences in intrinsic electrical properties of PVT neurons recorded in slices from different ZT periods. In night period slices, neurons have a more depolarized resting membrane potential (RMP), lower resting membrane conductance, in part owing to lower overall K⁺ currents (I_K), and larger amplitude T-type Ca²⁺ (I_T) and hyperpolarization-activated cation (I_H) currents. These changes result in increased spontaneous tonic and burst firing, and enhanced recurrent activity subsequent to generation of a low-threshold spike (LTS). For details, see Kolaj et al. (2012).

Figure 2

PVT neurons express unique T-type Ca²⁺ channel-mediated intracellular calcium profiles, and sAHPs. (A) On the left, a typical Ca²⁺ response profile in a single PVT neuron displays a fast and a slow phase of the Ca²⁺ signal in response to a single voltage pulse that activates T-type Ca²⁺ channels. On the right, average trace from 12 neurons that exhibit Ca²⁺ response profiles consistent with calcium-induced calcium release (CICR) in response to repetitive activation of T-type Ca²⁺ channels. (B) For contrast, trace from a single nRT neuron (left) exhibits no slow Ca²⁺ response and average trace from 13 neurons (right) shows no evidence of CICR. For details, see Richter et al. (2005). (C) Distribution of thalamic neurons that did (blue circles) or did not (gray circles) exhibit CICR in response to repetitive activation of T-type Ca²⁺ channels. Abbreviations and scheme are based on the rat atlas by Paxinos and Watson (1998) (Reproduced in part with permission from Richter et al., 2005). (D) Voltage traces from the same PVT neuron illustrate a spike train-induced (left) and an LTS-induced (right) sAHP (shaded areas). (E, F) Using similar protocols, representative traces indicate that similar sAHPs are not observed in ventrobasal (VB; black trace and symbols) or reticular thalamic (nRT; gray trace and symbols) neurons. (G) Distribution of tested neurons to depict that only cells in midline and intralaminar thalamus displayed sAHPs (red circles). Abbreviations and scheme are based on the rat atlas by Paxinos and Watson (1998) (Reproduced in part with permission from Zhang et al., 2010).

Figure 3

Some potential consequences of glutamate and orexin co-release at a synapse in PVT. On the left, microphotograph of coronal section from rat brain (bregma ∼ −3.14) reveal a dense distribution of orexin A-immunoreactive fibers in PVT nucleus. Abbreviations: D3v, dorsal 3rd ventricle; MHb, medial habenula. On the right, schematic synapse depicting action potential invasion of an axon terminal in PVT containing storage vesicles for a rapid transmitter (glutamate, red symbols) and a neuropeptide (orexin A or B, green symbols). Presynaptically released glutamate diffuses across the synaptic cleft to act at postsynaptic ionotropic AMPA and NMDA receptors, promoting cation influx and induction of rapid excitatory postsynaptic currents. In addition, glutamate release may potentially activate metabotropic group II (mGluR-II) receptors to open pre- and/or postsynaptic K⁺ channels (Hermes and Renaud, 2011). Activity-dependent co-release of orexins and activation of metabotropic orexin receptors (orexinR1/2) may have several postsynaptic actions that collectively result in enhanced neuronal excitability by: (a) opening of nonselective cation channels (NSCC; Kolaj et al., 2007); (b) closing of K⁺ channels, including two-pore-domain TASK-like channels that are constitutively active at rest (Doroshenko and Renaud, 2009); and (c) suppression of K_Ca and K_Na channels underlying spike train induced sAHPs (Zhang et al., 2010).