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  • Medium spiny neurons MSNs in the striatum

    2023-11-18

    Medium spiny neurons (MSNs) in the striatum start from a deeply hyperpolarized resting membrane potential, slowly depolarize and show a delayed start of firing during a current injection (Kawaguchi, 1993, Nisenbaum and Wilson, 1995, Planert et al., 2013). The firing pattern during the current injection is basically regular without transient burst firing and the firing rate is relatively low (20–40Hz maximum in vivo (Gage et al., 2010)). In vivo behavioral studies indicate that MSNs responsive during a task may not be responsive outside of that task (Aldridge and Berridge, 1998, Gardiner and Kitai, 1992). The firing rate is progressively increased after task related cues and events that lead to action selection and reward, and the increased firing continues for several hundred milliseconds to several seconds (Barnes et al., 2011, Gage et al., 2010, Schmitzer-Torbert and Redish, 2008). Although prolonged activities of MSNs in animals executing a task progressively become clear, the adrenergic modulation for firing patterns is still unclear. For the induction of continuous striatal firing, we employed a transgenic rat which expresses channelrhodopsin-2 (ChR2) in neuronal Z-YVAD-FMK (Ji et al., 2012, Tomita et al., 2009). Although patch-clamp is the established intracellular recording method for observing current injection induced firings and electrically stimulated synaptic potentials, it is overly time-consuming for obtaining a large number of stable data, especially from mature, fully-developed animals. Therefore, we used the optogenetic stimulation and multi-unit extracellular spike recording technique in order to comprehensively grasp the firing modulation from hundreds of adult rat neurons. Surprisingly, repetitive optogenetic stimulation with 20-s stimulation onset intervals increased the number of spikes during and after the photostimulation (hereinafter “the firing increment”, the definition is in Materials and Methods). Since the firing increment might be related to the striatal function such as learning of action timing control (Doya, 1999, Houk et al., 1995, Jin et al., 2014, Tanaka and Kunimatsu, 2011), we utilized it as an index for the evaluation of adrenergic modulation on the striatum. As a result, we found that β- vs. α1-AR agonists and adrenaline vs. noradrenaline have opposing effects on the striatal firing pattern.
    Materials and methods
    Results
    Discussion We found that β-AR vs. α1-AR agonists and adrenaline vs. noradrenaline have opposing effects on striatal firing. Photostimulation to the W-TChR2V4 rat striatum induced a slow decaying depolarization (Fig. 1D). The 8–20s cycle repetitive photostimulation induced a firing increment (Figs. 1C, 2 and 3) and residual effects after a 20-s intermission (Fig. 4C). We utilized these phenomena to evaluate the adrenergic receptor modulation on the striatum. As a result, β-agonist isoproterenol and adrenaline increased the early phase firing response and isoproterenol decreased the post phase firing response (Fig. 6, Fig. 8), while α1-agonist phenylephrine and noradrenaline decreased the early phase firing response (Fig. 7, Fig. 8). Moreover, isoproterenol inhibited the late phase firing increment (Fig. 6, Fig. 8), while phenylephrine increased the late and post phase firing increment (Fig. 7, Fig. 8). This implies that the activation pattern of adrenergic receptors may influence timing-control related striatal processes: motor control and action sequence learning by reward (Doya, 1999, Houk et al., 1995, Jin et al., 2014), as well as the pathophysiology of the PD symptoms: movement and executive function disorders (Cameron et al., 2010, Fogelson et al., 2011). Although Venus fluorescence with ChR2 was broadly observed in the striatum (Fig. 1A), the precise cell-type specific ChR2 expression in the striatum has not yet been identified. However, we confirmed the ChR2 oriented response in MSN by using the patch-clamp method (Fig. 1B–E). The blocking of AMPA/NMDA receptors revealed that photostimulation to the striatum results in the activation both of the pre-synaptic glutamatergic fibers and post-synaptic direct depolarization (Fig. 5). The post-synaptic direct depolarization possibly comes from dendritic ChR2 activation, because the slow decaying depolarization was observed only after photostimulation (Fig. 1E) but not after current injection (Fig. 1G).