No abstract

As a common psychiatric disorder in the growing geriatric population, late-life depression (LLD) has a negative impact on the cognitive, affective, and somatic domains of the lives of the elderly individuals. Accumulating evidence from the structural and functional imaging studies on LLD supports a "network dysfunction model" rather than a "lesion pathology model" for understanding the underlying biological mechanism in this mental disorder. In this work, we used network dysfunction model as a conceptual framework for reviewing recent neuroimaging findings in LLD. Our focus was on 4 major neurocircuits that have been shown to be involved in LLD: default mood network, cognitive control network, affective/frontolimbic network, and corticostriatal circuits. Findings of LLD-related gray and white matter structural abnormalities and resting-state and task-based functional changes were discussed for each network separately. We extended our review by summarizing the latest works that apply graph theory-based network analysis techniques for testing alterations in whole-brain network properties associated with LLD.

Non-technical summary The property of excitability is conferred to specific cell types through the action of a host of ion channels. Two classes of ion channels which play crucial roles in cellular excitability are T-type calcium and hyperpolarization-activated cyclic-nucleotide (HCN) channels. Given that T-type and HCN channel availability is increased upon hyperpolarization, T-type-and HCN-mediated currents are critical determinants of rebound depolarizations in many cell types. Rebound responses have long been documented in deep cerebellar nuclear (DCN) neurons; however, the extent to which T-type-and HCN-mediated currents contribute to rebound depolarizations following physiological input has not been established. Using a combination of in vitro electrophysiological and in silico techniques, we define the roles of T-type-and HCN-mediated currents in controlling the frequency and latency of DCN rebound spike output. Our study demonstrates that T-type and HCN channels become sufficiently available during physiological levels of hyperpolarization to make distinct contributions to the frequency and latency of rebound responses. AbstractThe ability for neurons to generate rebound bursts following inhibitory synaptic input relies on ion channels that respond in a unique fashion to hyperpolarization. Inward currents provided by T-type calcium channels (I T ) and hyperpolarization-activated HCN channels (I H ) increase in availability upon hyperpolarization, allowing for a rebound depolarization after a period of inhibition. Although rebound responses have long been recognized in deep cerebellar nuclear (DCN) neurons, the actual extent to which I T and I H contribute to rebound spike output following physiological levels of membrane hyperpolarization has not been clearly established. The current study used recordings and simulations of large diameter cells of the in vitro rat DCN slice preparation to define the roles for I T and I H in a rebound response. We find that physiological levels of hyperpolarization make only small proportions of the total I T and I H available, but that these are sufficient to make substantial contributions to a rebound response. At least 50% of the early phase of the rebound spike frequency increase is generated by an I T -mediated depolarization. An additional frequency increase is provided by I H in reducing the time constant and thus the extent of I T inactivation as the membrane returns from a hyperpolarized state to the resting level. An I H -mediated depolarization creates an inverse voltage-first spike latency relationship and produces a 35% increase in the precision of the first spike latency of a rebound. I T and I H can thus be activated by physiologically relevant stimuli and have distinct roles in the frequency, timing and precision of rebound responses.

We investigated the regulation of T-type channels by Rho-associated kinase (ROCK). Activation of ROCK via the endogenous ligand lysophosphatidic acid (LPA) reversibly inhibited the peak current amplitudes of rat Ca(v)3.1 and Ca(v)3.3 channels without affecting the voltage dependence of activation or inactivation, whereas Ca(v)3.2 currents showed depolarizing shifts in these parameters. LPA-induced inhibition of Ca(v)3.1 was dependent on intracellular GTP, and was antagonized by treatment with ROCK and RhoA inhibitors, LPA receptor antagonists or GDPssS. Site-directed mutagenesis of the Ca(v)3.1 alpha1 subunit revealed that the ROCK-mediated effects involve two distinct phosphorylation consensus sites in the domain II-III linker. ROCK activation by LPA reduced native T-type currents in Y79 retinoblastoma and in lateral habenular neurons, and upregulated native Ca(v)3.2 current in dorsal root ganglion neurons. Our data suggest that ROCK is an important regulator of T-type calcium channels, with potentially far-reaching implications for multiple cell functions modulated by LPA.

Neurons of the deep cerebellar nuclei (DCN) play a critical role in defining the output of cerebellum in the course of encoding Purkinje cell inhibitory inputs. The earliest work performed with in vitro preparations established that DCN cells have the capacity to translate membrane hyperpolarizations into a rebound increase in firing frequency. The primary means of distinguishing between DCN neurons has been according to cell size and transmitter phenotype, but in some cases, differences in the firing properties of DCN cells maintained in vitro have been reported. In particular, it was shown that large diameter cells in the rat DCN exhibit two phenotypes of rebound discharge in vitro that may eventually help define their functional roles in cerebellar output. A transient burst and weak burst phenotype can be distinguished based on the frequency and pattern of rebound discharge immediately following a hyperpolarizing stimulus. Work to date indicates that the difference in excitability arises from at least the degree of activation of T-type Ca2+ current during the immediate phase of rebound firing and Ca2+-dependent K+ channels that underlie afterhyperpolarizations. Both phenotypes can be detected following stimulation of Purkinje cell inhibitory inputs under conditions that preserve resting membrane potential and natural ionic gradients. In this paper, we review the evidence supporting the existence of different rebound phenotypes in DCN cells and the ion channel expression patterns that underlie their generation.