Slow Wave Sleep Deficits in the Flinders Sensitive Line Rodent Model of Depression: Effects of Medial Forebrain Bundle Deep-Brain Stimulation

Highlights

• FSL rats recapitulate sleep depression-related sleep abnormalities.

• Slow-wave sleep abnormalities include hippocampal ripples and cortical spindles.

• Medial forebrain bundle deep-brain stimulation alleviates behavioural deficits only.

Abstract

Major Depressive Disorder (MDD) is an affective disorder typically accompanied by sleep disturbances. Deep brain stimulation (DBS) of the medial forebrain bundle (MFB) is an emerging intervention for treatment-resistant depression, but its effect on sleep has not been closely examined. Here we aimed to characterise sleep deficits in the Flinders sensitive line, an established rodent model of depression, and investigate the consequences of MFB stimulation on sleep-related phenotypes. Rats were implanted with bilateral stimulation electrodes in the MFB, surface electrodes to record electrocorticography and electromyography for sleep scoring and electrodes within the prelimbic cortex, nucleus accumbens (NAc) and dorsal hippocampus. Recordings of sleep and oscillatory activity were conducted prior to and following twenty-four hours of MFB stimulation. Behavioural anti-depressant effects were monitored using the forced swim test. Previously unreported abnormalities in the Flinders sensitive line rats were observed during slow wave sleep, including decreased circadian amplitude of its rhythm, a reduction in slow wave activity and elevated gamma band oscillations. Previously established rapid eye movement sleep deficits were replicated. MFB stimulation had anti-depressant effects on behavioural phenotype, but did not significantly impact sleep architecture; it suppressed elevated gamma activity during slow wave sleep in the electrocorticogram and prelimbic cortex signals. Diverse abnormalities in Flinders sensitive line rats emphasise slow wave sleep as a state of dysfunction in affective disorders. MFB stimulation is able to affect behaviour and sleep physiology without influencing sleep architecture. Gamma modulation may represent a component of antidepressant mechanism.

Introduction

Major Depressive Disorder (MDD, depression) is a common and complex mental disorder comprising many heterogeneous aspects, with inter-patient variation in onset, symptoms and treatment response. Depression is characterised by low mood, reduced motivation and diminished feelings of interest and pleasure, but encompasses a variety of other behavioural and physiological symptoms, notably sleep disturbance (Riemann et al., 2001, Argyropoulos and Wilson, 2005, Kennedy, 2008, Bentley et al., 2014). Sleep and depression share a strong, likely bi-directional relationship. Sleep deficits, manifesting primarily as insomnia, affect over 80% of patients (Yates et al., 2007). Sleep disturbance strongly affects quality of life for depressed patients and is a predictor of suicide risk (Ağargün et al., 1997, Mayers et al., 2003). Patients suffer worse subjective sleep quality alongside physiological changes to the structure of sleep (sleep architecture) and underlying processes; these include a reduction of slow wave sleep (SWS) and a disinhibition of REM sleep, manifesting as reduced latency to rapid eye movement (REM) sleep, prolongation of early REM periods and increased density of eye movements (Riemann et al., 2001, Nutt et al., 2008, Baglioni et al., 2016). These problems are often prodromal relative to other symptoms, and are commonly residual after treatment, a factor which is associated with the occurrence of future episodes (Baglioni et al., 2011, McClintock et al., 2011, Fang et al., 2019). Sleep is therefore a vital consideration in terms of experimental treatments for severe depression. Whereas almost all antidepressant drugs suppress REM sleep (Riemann et al., 2001, Wichniak et al., 2017), some of them actually worsen sleep (Argyropoulos and Wilson 2005). Given the role of sleep disruption in predicting relapse (Tranter et al., 2002), there is a strong argument to emphasise the importance of sleep restoration in the treatment of MDD.

A significant minority of patients – estimated up to 30% (Rush et al., 2006) — do not respond to conventional treatments. For this treatment resistant depression (TRD), experimental therapies are being developed including deep brain stimulation (DBS), by which electrical current is delivered through surgically implanted electrodes to selected brain targets (Mayberg et al., 2005, Schlaepfer et al., 2013). One such target for DBS is the medial forebrain bundle (MFB; capital letters are used here to refer to the human MFB, and lower case used for the rodent mfb), a highly connected fibre tract running between midbrain and forebrain structures, and containing, among others, dopaminergic, serotonergic and glutamatergic fibres (Coenen et al., 2011, Coenen et al., 2012, Coenen et al., 2018b, Döbrössy et al., 2021). Ascending components from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and pre-frontal cortex (PFC) have been implicated in motivation and reward orientated behaviours. DBS of the superolateral branch of the MFB (slMFB, that in humans encompasses the ascending VTA projections) has been the subject of promising clinical trials in TRD patients (Schlaepfer et al., 2013, Fenoy et al., 2016, Fenoy et al., 2018, Bewernick et al., 2017a, Bewernick et al., 2017b, Coenen et al., 2018a, Coenen et al., 2019). The MFB network contains neural systems implicated in sleep, and while there is some anecdotal evidence of improved perception of sleep quality after slMFB–DBS (private correspondence, FORSEE study team), no specific investigation into the effects of MFB–DBS on sleep has been conducted.

The Flinders Sensitive Line (FSL) rat is a model of genetic predisposition to depression, exhibiting spontaneous and stress-sensitive depressive-like phenotypes (Friedman et al., 2008, Overstreet and Wegener, 2013, Edemann-Callesen et al., 2015, Voget et al., 2015, Thiele et al., 2016), including decreased latency to REM sleep (Shiromani et al., 1988, Benca et al., 1996) which suggests a suitable model for sleep-related symptoms in depression. In the FSL, mfb–DBS has been shown to have anti-depressant-like effects on behaviour (Edemann-Callesen et al., 2015, Thiele et al., 2018) and physiology (Ashouri Vajari et al., 2020). The current experiments aimed to better characterise the baseline sleep phenotype of the FSL, and investigate the effects of mfb–DBS upon sleep-related parameters. Electrophysiological recordings of the NAc, pre-limbic cortex (PrL) of the PFC, and dorsal CA1 hippocampus (CA1) were made in addition to standard ECoG/EMG recordings during sleep, before and after 24-h of mfb–DBS. Behavioural phenotype was measured via the forced swim test (FST), in order to confirm the anti-depressant action of mfb–DBS. Previously reported REM disinhibition was replicated, while FSL rats also displayed circadian-related alterations to SWS architecture and abnormal physiology including reduced activity in the delta band, elevated gamma activity, modifications of hippocampal ripple features and spindle activity. mfb–DBS had an anti-depressant effect on behaviour in the FST and suppressed elevated gamma oscillations during SWS, but had no notable effect on sleep architecture and other oscillatory activities.