Daily variation in the electrophysiological activity of mouse medial habenula neurones

Abstract

Intrinsic daily or circadian rhythms arise through the outputs of the master circadian clock in the brain's suprachiasmatic nuclei (SCN) as well as circadian oscillators in other brain sites and peripheral tissues. SCN neurones contain an intracellular molecular clock that drives these neurones to exhibit pronounced day–night differences in their electrical properties. The epithalamic medial habenula (MHb) expresses clock genes, but little is known about the bioelectric properties of mouse MHb neurones and their potential circadian characteristics. Therefore, in this study we used a brain slice preparation containing the MHb to determine the basic electrical properties of mouse MHb neurones with whole-cell patch clamp electrophysiology, and investigated whether these vary across the day–night cycle. MHb neurones (n = 230) showed heterogeneity in electrophysiological state, ranging from highly depolarised cells (∼ −25 to −30 mV) that are silent with no membrane activity or display depolarised low-amplitude membrane oscillations, to neurones that were moderately hyperpolarised (∼40 mV) and spontaneously discharging action potentials. These electrical states were largely intrinsically regulated and were influenced by the activation of small-conductance calcium-activated potassium channels. When considered as one population, MHb neurones showed significant circadian variation in their spontaneous firing rate and resting membrane potential. However, in recordings of MHb neurones from mice lacking the core molecular circadian clock, these temporal differences in MHb activity were absent, indicating that circadian clock signals actively regulate the timing of MHb neuronal states. These observations add to the extracellularly recorded rhythms seen in other brain areas and establish that circadian mechanisms can influence the membrane properties of neurones in extra-SCN sites. Collectively, the results of this study indicate that the MHb may function as an intrinsic secondary circadian oscillator in the brain, which can shape daily information flow in key brain processes, such as reward and addiction.

Regulation of persistent sodium currents by glycogen synthase kinase 3 encodes daily rhythms of neuronal excitability

“…Based on the results, SCN neurons were classified as either (i) silent, (ii) spiking, (iii) having depolarized electrical states with low-amplitude membrane oscillations or (iv) exhibiting depolarization block, in which spiking could be reinstated by injecting hyperpolarizing current (Supplementary Fig. 2) as reported in other brain areas2021 as well as in the SCN16. In the remaining spontaneously spiking neurons, APs were separated (or generated) by smooth depolarizing ramps to threshold (Fig.…”

Acute Suppressive and Long-Term Phase Modulation Actions of Orexin on the Mammalian Circadian Clock

“…These findings support the view that in vertebrates, orexin signaling plays pivotal roles in the timing of transitions in brain and behavioral states (Mochizuki et al, 2004;Elbaz et al, 2012). Since the neural circadian system is extensive (Sakhi et al, 2013) and because orexin neurons innervate many components of this circadian timing circuitry (Peyron et al, 1998), it is important to understand how orexin signaling integrates with circadian time cues to influence neuronal activity in these areas. A key implication is that the mechanisms of orexin's actions in the SCN switch from predominantly GABA-mediated presynaptic actions during the day to robust direct postsynaptic effects at night.…”

Temporal variations in presynaptic release probability in the lateral habenula

“…Some studies reported that temporal variations in the habenula complex was limited to the LHb1320 however, recently, the medial habenular neurons are also shown to exhibit daily variations similar to our observations. In this study, daily variations were no longer observed in clock gene deficient animals, suggesting that the temporal dynamics could be directly regulated by the expression of clock-related genes34. Thus, the excitability of the entire habenula complex is likely under the circadian control.…”

“…More importantly, the variations include a significant shift in the dominance of highly active population of neurons and primarily rise from presynaptic efficacy of neurotransmitter release. This is of particular interest given that the LHb activity in animal models of depression were presynaptically but not postsynaptically potentiated and the high-frequency neurons are likely to make greater contribution to the observed abnormal potentiation in helpless rodent models34.…”

“…Blockade of neuronal activity by tetrodotoxin (TTX) treatment failed to alter the circadian variations observed in the LHb12. The temporal variations in firing rates in the LHb12 and the mHb34 were not observed in animals lacking core circadian clock genes. What then may be the underlying cellular mechanisms mediating temporal variations in release probability in LHb synapses?…”