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    • Rising depolarization was observed during and

    2024-03-26

    Rising depolarization was observed during and decaying depolarization after the photostimulation (Fig. 1D). The slow decrease of the firing rate after photostimulation is also a remarkable characteristic of the striatal neuron (Figs. 1E, 2 and 3), since the cortex pyramidal neurons (data not shown) and the hippocampus CA1 pyramidal neurons (Ohta et al., 2013) show a firing pattern strictly matching the photostimulation duration without any responses after the photostimulation. In MSNs, prolonged dendritic calcium activation which is correlated to the sustained depolarization “upstate” was reported (Day et al., 2008, Kerr and Plenz, 2004, Kerr and Plenz, 2002, Kitano et al., 2002, Plenz and Kitai, 1998, Plotkin et al., 2011, Wilson and Kawaguchi, 1996). It was also reported that depolarizing stimulus upregulates the probability of spike generation after several hundred ms (Mahon et al., 2003, Mahon et al., 2000a, Mahon et al., 2000b, Onn et al., 1994). However, there were no obvious reports of the sustained continuous firings in slice preparations and the deca-second order sustained mode changes. To this, we discovered the firing increment induced by the 8–20-s cycle repetitive stimulations (Figs. 3A–C) and the residual effect after the 20-s intermission (Fig. 4C). We observed the slow depolarization decay with an 8.6-s half-life (Fig. 1D) and the accumulation of the residual depolarization after the repetitive photostimulations (Fig. 1E). The firing increment and the residual effect are possibly due to a lack of leak allopurinol zyloprim australia (e.g. hyperpolarization-activated cyclic nucleotide-gated channel) (Monteggia et al., 2000, Ohta, 2015). We demonstrated that isoproterenol and adrenaline increase the early phase firing response (Fig. 6A and B), while propranolol inhibits the adrenaline induced enhancement of the early phase firing response (Fig. 6C). Although β-ARs are found on striatal postsynaptic membranes and cell bodies (Hara et al., 2010, Nicholas et al., 1996, Paschalis et al., 2009, Pisani et al., 2003), the precise roles are not known. In the hippocampus, it is reported that the activation of β-ARs modulate synaptic inputs (Dunwiddie et al., 1992, Katsuki et al., 1997). Since the early phase firing response is related to the glutamatergic inputs (Fig. 5), the β-ARs could be related to the amplification of the transient synaptic inputs. Phenylephrine inhibited the early phase firing response and potentiated the late and post phase firing increment (Fig. 7A). Noradrenaline inhibited the early phase firing response (Fig. 7B). These data signify that the α1-AR affects the striatum by delaying firing initiation and enhancing continued firing. Recently, it has been reported that noradrenaline drives persistent activity in rat prefrontal cortex via α1- and α2-ARs (Zhang et al., 2013). Although, at this moment, the precise roles of α1-AR in the striatum are unknown, the enhancement of the late and post phase firing increment by phenylephrine is consistent with these reports. Noradrenergic/adrenergic as well as dopaminergic alterations have come to be regarded as important factors of PD symptoms (Delaville et al., 2011, LeWitt, 2012, Ostock and Bishop, 2014). The administration of β-agonist isoproterenol aggravates tremors in PD patients (Constas, 1962). Conversely, it is also thought that β-antagonist may be of use in controlling the tremors (Crosby et al., 2003). β-antagonist nadolol appears to be an effective adjunct to dopaminergic and anticholinergic therapy for severe tremors in PD (Foster et al., 1984). β-antagonist propranolol was claimed to reduce essential tremor (Winkler and Young, 1971) and l-DOPA-induced dyskinesia in PD patients (Carpentier et al., 1996). The antidyskinetic effects of propranolol have also been supported in rat studies (Barnum et al., 2012, Lindenbach et al., 2011). In sum, β-activation exacerbates while β-inhibition alleviates these movement disorders. In PD patients, CSF noradrenaline levels have been found to be decreased (Eldrup et al., 1995, Martignoni et al., 1992). The reduction of noradrenaline concentration in CSF of PD patients is significantly correlated with parkinsonian symptoms: the severity of Hoehn and Yahr's stage, akinesia and freezing of gait (Tohgi et al., 1993). The activation of LC, which contains noradrenergic neurons, may inhibit striatal firings in cat, and l-threo-dihydroxyphenylserine (l-DOPS), anoradrenaline precursor, lifts the inhibition (Hirose et al., 1988). l-DOPS is known to inhibit l-3,4-dihydroxyphenylalanine (l-DOPA) treatment-induced freezing of gait in humans. In dopamine-depleted rats, striatal noradrenaline loss exacerbates l-DOPA-induced dyskinesias (Fulceri et al., 2007). These reports consistently indicate that the recovery of decreased noradrenaline levels is important to control PD related symptoms. On the other hand, CSF adrenaline levels in PD were rarely reported. Tohgi et al. (1993) reported the increased levels of adrenaline in PD patients with dementia. Chia et al. (1993) also reported the increased adrenaline in l-DOPA-untreated and l-DOPA-withdrawn PD patients. These reports lead to the suggestion that the noradrenergic (and possibly adrenergic) modulations are important factors in PD.