Circadian Disruptions in the Myshkin Mouse Model of Mania Are Independent of Deficits in Suprachiasmatic Molecular Clock Function

Abstract

BackgroundAlterations in environmental light and intrinsic circadian function have strong associations with mood disorders. The neural origins underpinning these changes remain unclear, although genetic deficits in the molecular clock regularly render mice with altered mood-associated phenotypes.MethodsA detailed circadian and light-associated behavioral characterization of the Na+/K+-ATPase α3 Myshkin (Myk/+) mouse model of mania was performed. Na+/K+-ATPase α3 does not reside within the core circadian molecular clockwork, but Myk/+ mice exhibit concomitant disruption in circadian rhythms and mood. The neural basis of this phenotype was investigated through molecular and electrophysiological dissection of the master circadian pacemaker, the suprachiasmatic nuclei (SCN). Light input and glutamatergic signaling to the SCN were concomitantly assessed through behavioral assays and calcium imaging.ResultsIn vivo assays revealed several circadian abnormalities including lengthened period and instability of behavioral rhythms, and elevated metabolic rate. Grossly aberrant responses to light included accentuated resetting, accelerated re-entrainment, and an absence of locomotor suppression. Bioluminescent recording of circadian clock protein (PERIOD2) output from ex vivo SCN revealed no deficits in Myk/+ molecular clock function. Optic nerve crush rescued the circadian period of Myk/+ behavior, highlighting that afferent inputs are critical upstream mediators. Electrophysiological and calcium imaging SCN recordings demonstrated changes in the response to glutamatergic stimulation as well as the electrical output indicative of altered retinal input processing.ConclusionsThe Myshkin model demonstrates profound circadian and light-responsive behavioral alterations independent of molecular clock disruption. Afferent light signaling drives behavioral changes and raises new mechanistic implications for circadian disruption in affective disorders.

The Oxidative Status and Na+/K+-ATPase Activity in Obsessive-Compulsive Disorder: A Case Control Study

“…OCD can also be considered as a prototypical compulsivity disorder and kind of "behavioral addiction" [61,62]. Numerous investigations have shown elicited behavioral alterations due to mutations in Na + /K + -ATPase isoform [24,[63][64][65][66][67][68][69]. Overall, data support the role of Na + / K + -ATPase activity in determining behavior.…”

The Oxidative Status and Na+/K+-ATPase Activity in Obsessive-Compulsive Disorder: A Case Control Study

“…OCD can also be considered as a prototypical compulsivity disorder and kind of "behavioral addiction" [61,62]. Numerous investigations have shown elicited behavioral alterations due to mutations in Na + /K + -ATPase isoform [24,[63][64][65][66][67][68][69]. Overall, data support the role of Na + / K + -ATPase activity in determining behavior.…”

Loss of neuropeptide signalling alters temporal expression of mouse suprachiasmatic neuronal state and excitability

“…To investigate how the electrical state and membrane properties of Vipr2 +/+ SCN neurons vary across the projected LD cycle and to determine if and how these properties are altered in Vipr2 −/− mice, we made whole‐cell current clamp recordings from SCN brain slices. Using previously published protocols (Belle et al, 2009, 2014; Timothy et al, 2018; Wegner et al, 2017) we classified the spontaneous activity of SCN cells into one of three states: 1) depolarized and not discharging action potentials (silent) or with DLAMOs, 2) spontaneously discharging action potentials (APs) and 3) hyperpolarized and silent (Figure 1d). Circadian clock gene expression is damped in the Vipr2 −/− SCN in vivo (Harmar et al, 2002; Hitrec et al, 2023), and consistent with previous reports (Hughes et al, 2008; Maywood et al, 2006).…”

Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus

“…Do certain types of SCN disruptions cause mood changes? As discussed, genetic perturbations in mice can produce period changes, amplitude reductions, increased sensitivity to photic phase shifts, and mood-like disturbances [ 183 , 327 , 329 , 332 , 333 , 335 , 339 ]. Importantly, shifted rhythms, dampened rhythms, and light hypersensitivity have been found in some individuals with mood disorders [ 50 , 88 , 91 ].…”

The Oxidative Status and Na+/K+-ATPase Activity in Obsessive-Compulsive Disorder: A Case Control Study

“…OCD can also be considered as a prototypical compulsivity disorder and kind of "behavioral addiction" [61,62]. Numerous investigations have shown elicited behavioral alterations due to mutations in Na + /K + -ATPase isoform [24,[63][64][65][66][67][68][69]. Overall, data support the role of Na + / K + -ATPase activity in determining behavior.…”

Loss of neuropeptide signalling alters temporal expression of mouse suprachiasmatic neuronal state and excitability

“…To investigate how the electrical state and membrane properties of Vipr2 +/+ SCN neurons vary across the projected LD cycle and to determine if and how these properties are altered in Vipr2 −/− mice, we made whole‐cell current clamp recordings from SCN brain slices. Using previously published protocols (Belle et al, 2009, 2014; Timothy et al, 2018; Wegner et al, 2017) we classified the spontaneous activity of SCN cells into one of three states: 1) depolarized and not discharging action potentials (silent) or with DLAMOs, 2) spontaneously discharging action potentials (APs) and 3) hyperpolarized and silent (Figure 1d). Circadian clock gene expression is damped in the Vipr2 −/− SCN in vivo (Harmar et al, 2002; Hitrec et al, 2023), and consistent with previous reports (Hughes et al, 2008; Maywood et al, 2006).…”

Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus

“…Do certain types of SCN disruptions cause mood changes? As discussed, genetic perturbations in mice can produce period changes, amplitude reductions, increased sensitivity to photic phase shifts, and mood-like disturbances [ 183 , 327 , 329 , 332 , 333 , 335 , 339 ]. Importantly, shifted rhythms, dampened rhythms, and light hypersensitivity have been found in some individuals with mood disorders [ 50 , 88 , 91 ].…”

The Oxidative Status and Na+/K+-ATPase Activity in Obsessive-Compulsive Disorder: A Case Control Study

“…OCD can also be considered as a prototypical compulsivity disorder and kind of "behavioral addiction" [61,62]. Numerous investigations have shown elicited behavioral alterations due to mutations in Na + /K + -ATPase isoform [24,[63][64][65][66][67][68][69]. Overall, data support the role of Na + / K + -ATPase activity in determining behavior.…”

Loss of neuropeptide signalling alters temporal expression of mouse suprachiasmatic neuronal state and excitability

“…To investigate how the electrical state and membrane properties of Vipr2 +/+ SCN neurons vary across the projected LD cycle and to determine if and how these properties are altered in Vipr2 −/− mice, we made whole‐cell current clamp recordings from SCN brain slices. Using previously published protocols (Belle et al, 2009, 2014; Timothy et al, 2018; Wegner et al, 2017) we classified the spontaneous activity of SCN cells into one of three states: 1) depolarized and not discharging action potentials (silent) or with DLAMOs, 2) spontaneously discharging action potentials (APs) and 3) hyperpolarized and silent (Figure 1d). Circadian clock gene expression is damped in the Vipr2 −/− SCN in vivo (Harmar et al, 2002; Hitrec et al, 2023), and consistent with previous reports (Hughes et al, 2008; Maywood et al, 2006).…”

Circadian Rhythm Disturbances in Mood Disorders: Insights into the Role of the Suprachiasmatic Nucleus

“…Do certain types of SCN disruptions cause mood changes? As discussed, genetic perturbations in mice can produce period changes, amplitude reductions, increased sensitivity to photic phase shifts, and mood-like disturbances [ 183 , 327 , 329 , 332 , 333 , 335 , 339 ]. Importantly, shifted rhythms, dampened rhythms, and light hypersensitivity have been found in some individuals with mood disorders [ 50 , 88 , 91 ].…”