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.
Highlights
Near-24 h or circadian rhythms in physiology and behaviour emerge through the activities of intrinsic circadian oscillators in the brain and body and their synchronisation to recurrent environment signals, including variation in environmental lighting, food availability and social interactions (Dibner et al 2010; Piggins & Guilding, 2011; Bechtold & Loudon, 2013)
In all subsequent recordings, no attempt was made to differentiate and target enhanced destabilised green fluorescent protein (EGFP)+ve and –ve neurones in the medial habenula (MHb). Since this is the first investigation of MHb neurones in mice, we describe the various states of MHb neurones with respect to their membrane properties, and subsequently discuss the circadian aspect of these electrical properties
We demonstrate that mouse MHb neurones exhibit unusual electrophysiological properties as well as circadian variation in their resting membrane potential (RMP) and firing rate characteristics
Summary
Near-24 h or circadian rhythms in physiology and behaviour emerge through the activities of intrinsic circadian oscillators in the brain and body and their synchronisation (entrainment) to recurrent environment signals, including variation in environmental lighting, food availability and social interactions (Dibner et al 2010; Piggins & Guilding, 2011; Bechtold & Loudon, 2013). The brain’s suprachiasmatic nuclei (SCN) house the dominant light-entrainable circadian clock, and many SCN neurones contain an intracellular molecular clock of which the Period (Per1–2) and Cryptochrome (Cry1–2) genes and their protein products (PER1–2, CRY1–2) are important constituents (Ko & Takahashi, 2006; Welsh et al 2010) This intracellular transcription–translation feedback loop completes a cycle in ß24 h and drives SCN neurones to show pronounced day–night differences in their electrical activity (Brown & Piggins, 2007; Colwell, 2011). The SCN was the first neural pacemaker to be identified in mammals, but evidence over the past 15 years establishes that other neural sites and peripheral tissues rhythmically express circadian clock genes (Guilding & Piggins, 2007; Dibner et al 2010) One such brain structure is the habenula (Hb) which is located above the dorsal thalamus (Herkenham & Nauta, 1979; Kim, 2009). These studies raise the possibility that circadian signals influence MHb neuronal activity
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