Research ArticleSlow Wave Sleep Deficits in the Flinders Sensitive Line Rodent Model of Depression: Effects of Medial Forebrain Bundle Deep-Brain Stimulation
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.
Section snippets
Animals and experimental design
Male FSL rats were sourced from the breeding colony maintained at the University Hospital Freiburg. Non-depressive controls were age- and sex-matched Sprague Dawley rats (Ctrl), sourced from Janvier Labs (France) (Overstreet, 2012). All animals were single housed from the start of the experimental timeline and kept under a 12 h/12 h light–dark cycle (Zeitbgeber Time (ZT) 0 corresponding to lights-on and ZT12 to lights-off), in a temperature (21 ± 2 °C) and humidity (50 ± 5%) controlled
Sleep architecture
ECoG and EMG recordings were used to assess sleep in controls and the FSL rats over 48 h baseline. In these measurements, FSL rats exhibited various abnormalities in sleep architecture compared to non-depressive controls. As predicted by earlier studies, FSL rats showed clear changes to REM sleep: they consistently spent more time overall in REM sleep over 24 h (two-way ANOVA, group factor F(1, 9) = 10.85, p = 0.0093, Fig. 3C), episodes of REM sleep in the FSL were more numerous (group factor F
Discussion
While sleep anomalies are strongly associated with depression, it is not known how the experimental treatment of slMFB–DBS affects these symptoms. The current study demonstrated abnormalities in the FSL rat in REM sleep architecture, the distribution of SWS and related delta activity, as well as elevated high-frequency gamma oscillations in ECoG signal and the NAc. 24 h mfb–DBS produced a behavioural anti-depressant effect, while normalising ECoG gamma oscillations and early-sleep delta
Ethical statement
The authors declare that animals were handled in accordance with ethical requirements enacted by the French authorities and the Strasbourg University who approved the present project (APAFIS #12113).
Author contributions
LL, MD, WG designed the study. LD, WG performed the experiments and analyzed the data. FF analyzed the data. WG, FF wrote the manuscript. MD, PB, LL corrected the manuscript.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgements
This work was supported by the NeuroTime Erasmus+ program of the European Commission. This publication reflects the views only of the authors, and the Commission cannot be held responsible for any use which may be made of the information contained therein.
References (85)
- et al.
High-Gamma: A biological marker for suicide attempt in patients with depression
J Affect Disord
(2019) - et al.
EEG gamma synchronization is associated with response to paroxetine treatment
J Affect Disord
(2018) - et al.
Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression
Exp Neurol
(2020) - et al.
Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies
J Affect Disord
(2011) - et al.
Increased basal REM sleep but no difference in dark induction or light suppression of REM sleep in flinders rats with cholinergic supersensitivity
Neuropsychopharmacology
(1996) - et al.
Major depression
Med Clin North Am
(2014) - et al.
Acute antidepressant effects of deep brain stimulation – Review and data from slMFB-stimulation
Personal Med Psychiatry
(2017) - et al.
Deep brain stimulation to the medial forebrain bundle for depression- long-term outcomes and a novel data analysis strategy
Brain Stimul
(2017) - et al.
Chronux: A platform for analyzing neural signals
J Neurosci Methods
(2010) - et al.
All-night spectral analysis of the sleep EEG in untreated depressives and normal controls
Psychiatry Res
(1984)
Antidepressant-like Effects of Medial Forebrain Bundle Deep Brain Stimulation in Rats are not Associated With Accumbens Dopamine Release
Brain Stimulation
Tractography-assisted deep brain stimulation of the superolateral branch of the medial forebrain bundle (slMFB DBS) in major depression
NeuroImage Clin
Cross-species affective functions of the medial forebrain bundle—Implications for the treatment of affective pain and depression in humans
Neurosci Biobehav Rev
The anatomy of the human medial forebrain bundle: Ventral tegmental area connections to reward-associated subcortical and frontal lobe regions
NeuroImage Clin
Medial forebrain bundle deep brain stimulation has symptom-specific anti-depressant effects in rats and as opposed to ventromedial prefrontal cortex stimulation interacts with the reward system
Brain Stimul: Basic Transl Clin Res Neuromodul
Estimation of the time course of slow-wave sleep over the night in depressed patients: Effects of clomipramine and clinical response
Biol Psychiatry
Somatostatin-positive gamma-aminobutyric acid interneuron deficits in depression: cortical microcircuit and therapeutic perspectives
Biol Psychiatry
Deep brain stimulation of the medial forebrain bundle: Distinctive responses in resistant depression
J Affect Disord
Inhibitory postsynaptic potentials carry synchronized frequency information in active cortical networks
Neuron
Deep brain stimulation of the medial forebrain bundle elevates striatal dopamine concentration without affecting spontaneous or reward-induced phasic release
Neuroscience
Antidepressant effects of selective slow wave sleep deprivation in major depression: a high-density EEG investigation
J Psychiatr Res
Reduced sleep spindle activity in early-onset and elevated risk for depression
J Am Acad Child Adolesc Psychiatry
Deep brain stimulation for treatment-resistant depression
Neuron
Serotonin control of sleep-wake behavior
Sleep Med Rev
The involvement of dopamine in the modulation of sleep and waking
Sleep Med Rev
Delta sleep ratio as a predictor of sleep deprivation response in major depression
J Psychiatr Res
The Flinders sensitive line rats: a genetic animal model of depression
Neurosci Biobehav Rev
The roles of the reward system in sleep and dreaming
Neurosci Biobehav Rev
Sleep and depression — results from psychobiological studies: An overview
Biol Psychol
Rapid effects of deep brain stimulation for treatment-resistant major depression
Biol Psychiatry
Diurnal rhythm of core body temperature is phase advanced ina rodent model of depression
Biol Psychiatry
Free-running period of circadian rhythms is shorter in rats with a genetically upregulated central cholinergic system
Biol Psychiatry
The effects of bilateral, continuous, and chronic Deep Brain Stimulation of the medial forebrain bundle in a rodent model of depression
Exp Neurol
Long-term characterization of the Flinders Sensitive Line rodent model of human depression: Behavioral and PET evidence of a dysfunctional entorhinal cortex
Behav Brain Res
An excitatory synapse hypothesis of depression
Trends Neurosci
Sleep and synaptic homeostasis: A hypothesis
Brain Res Bull
Sleep function and synaptic homeostasis
Sleep Med Rev
Altered local field potential activity and serotonergic neurotransmission are further characteristics of the Flinders sensitive line rat model of depression
Behav Brain Res
Sleep disturbances and suicidal behavior in patients with major depression
J Clin Psychiatry
Alterations in sleep, sleep spindle, and EEG power in mGluR5 knockout mice
J Neurophysiol
Sleep disturbances in depression and the effects of antidepressants
Int Rev Psychiatry
Sleep and mental disorders: a meta-analysis of polysomnographic research
Psychol Bull
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