Cortical Network Switching: Possible Role of the Lateral Septum and Cholinergic Arousal

doi:10.1016/j.brs.2014.09.003

Brain Stimulation

Volume 8, Issue 1, January–February 2015, Pages 36-41

https://doi.org/10.1016/j.brs.2014.09.003 Get rights and content

Highlights

•
In this study we propose and investigate the novel hypothesis that lateral septal activation may depress cortical activity through inhibition of subcortical cholinergic arousal.
•
We used simultaneous electrophysiology and high time-resolution amperometry to measure cortical choline levels as a marker of acetylcholinergic neurotransmission during lateral septal stimulation.
•
We found a decrease of choline levels in the cortex, along with cortical slow oscillations during lateral septal stimulation.
•
Our findings offer a new potential mechanism for initiating transitions in cortical activity through inhibitory subcortical regions (e.g. lateral septum) decreasing subcortical arousal (e.g. acetylcholine) which may have broad implications for both normal and abnormal cortical network function.

Abstract

Background

Cortical networks undergo large-scale switching between states of increased or decreased activity in normal sleep and cognition as well as in pathological conditions such as epilepsy. We previously found that focal hippocampal seizures in rats induce increased neuronal firing and cerebral blood flow in subcortical structures including the lateral septal area, along with frontal cortical slow oscillations resembling slow wave sleep. In addition, stimulation of the lateral septum in the absence of a seizure resulted in cortical deactivation with slow oscillations.

Hypothesis

We hypothesized that lateral septal activation might cause neocortical deactivation indirectly, possibly through impaired subcortical arousal. But how does subcortical stimulation cause slow wave activity in frontal cortex? How do arousal neurotransmitter levels (e.g. acetylcholine) change in cortex during the excitation of inhibitory projection nuclei?

Methods and results

In the current study, we used simultaneous electrophysiology and enzyme-based amperometry in a rat model, and found a decrease in choline, along with slow wave activity in orbital frontal cortex during lateral septal stimulation in the absence of seizures. In contrast, the choline signal and local field potential in frontal cortex had no significant changes when stimulating the hippocampus, but showed increased choline and decreased slow wave activity with an arousal stimulus produced by toe pinch.

Conclusions

These findings indicate that the activation of subcortical inhibitory structures (such as lateral septum) can depress subcortical cholinergic arousal. This mechanism may play an important role in large-scale transitions of cortical activity in focal seizures, as well as in normal cortical function.

Introduction

Cortical networks undergo large-scale transitions in activity during normal cognition and sleep as well as in brain disorders. Investigation of the mechanisms of large-scale network switching in the brain is an important emerging area of neuroscience research [1], [2], [3]. Prior work has shown that the transition to slow-wave sleep involves massive changes in cortical network activity accompanied by a decrease in neurotransmitters such as acetylcholine arising from subcortical arousal systems [4]. We have recently found similarities between onset of slow-waves in deep sleep and cortical slow wave activity observed during partial limbic seizures [5], [6], [7], [8]. The switching mechanism for these transitions is not well understood and still requires further investigation.

Circuits controlling subcortical arousal may play a critical role in regulating large-scale cortical transitions. Based on our findings in limbic seizures we proposed the “network inhibition hypothesis” [3], [9] in which increased activity in one region such as the hippocampus (HC) turns on inhibitory neurons in subcortical structures. GABAergic neurons in turn inhibit subcortical arousal leading to cortical slow-waves and decreased level of consciousness [10], [11]. We found using high-field functional magnetic resonance imaging (fMRI) that the lateral septal nuclei were strongly activated during hippocampal seizures, and that electrical stimulation of the lateral septal nuclei at 1–10 Hz produced a transition to cortical slow wave activity and behavioral arrest [7], [8]. Slow wave activity was prominent in multiple cortical areas including orbital frontal cortex (OFC).

But how does lateral septal activation cause cortical deactivation? Septal activation could contribute either via direct inhibition of neocortex or through diminished subcortical arousal. A long latency was detected from single septal stimuli to cortical Down states [8], consistent with a polysynaptic mechanism [12], [13]. In addition, the lateral septum (LS) does not have known direct projections to frontal cortex [14], [15]. The lateral septal nuclei receive their major inputs from the hippocampal formation, and then project to the medial septum, as well as to various hypothalamic areas, the mammillary complex, the ventral tegmental area, and other regions in the basal forebrain [14], [15], [16], [17]. Therefore, GABAergic neurons in the lateral septum are poised to produce inhibitory projections to subcortical arousal regions including the nucleus basalis, which in turn provides the major cholinergic supply to the cortex [17], [18], [19]. Hence, we propose that lateral septal activation can cause neocortical deactivation indirectly, through decreased subcortical arousal. Therefore, a crucial question is whether septal activation and the transition to cortical slow waves are associated with decreased cortical cholinergic activity.

To investigate this question we used simultaneous electrophysiology and high time-resolution amperometry to measure cortical choline levels as a marker of cholinergic neurotransmission during lateral septal stimulation. We found that the transition to cortical slow waves during septal stimulation was accompanied by a marked decrease in cortical choline. These findings support the network inhibition hypothesis, with increased lateral septal activity and reduced cholinergic neurotransmission as possible mechanisms for switching cortical networks to a state of decreased arousal.

Section snippets

Animal preparation, surgery and histology

All procedures were in full compliance with approved institutional animal care and use protocols. A total of 18 adult female Sprague Dawley rats (Charles River Laboratories) Weighing 230–300 g were used in the experiments. All surgeries were performed under anesthesia with ketamine (90 mg/kg) and xylazine (15 mg/kg, i.m.). Responsiveness was checked every 15 min by toe pinch. After surgery, animals were switched to a low-dose, “light-anesthesia” ketamine/xylazine (40/7 mg/kg) in preparation for

Lateral septal stimulation and toe pinch cause reciprocal changes in cortical delta power

We stimulated the lateral septum and hippocampus in lightly anesthetized rats for 60 s using 3 Hz stimulus trains below seizure threshold. We observed that lateral septal stimulation could induce large-amplitude neocortical slow waves (Fig. 1B). The slow wave activity had maximal power at about 1 Hz, which was not synchronous with the stimulus frequency (3 Hz). On average, stimulation of the lateral septum produced a significant elevation in cortical delta frequency LFP power compared to

Discussion

In the present study, we investigated choline signals in frontal cortex during lateral septal electrical stimulation in rats. We report, for the first time, a significant choline decrease along with synchronized slow oscillations in frontal cortex during lateral septal stimulation. These slow waves have been shown previously to include up and down states of neuronal firing similar to those seen in other states of depressed cortical function such as deep sleep, coma or limbic seizures [5], [6],

Acknowledgments

We thank Quanteon LLC for technical support for the amperometry measurements.

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Following LS lesion, Brady and Nauta (1953) originally described changes in “general emotional reactivity” (Brady and Nauta, 1953; see also Spiegel et al., 1940). Subsequently, different authors have attributed specific roles of the LS in anxiety (Chee and Menard, 2013; Parfitt et al., 2017), arousal (Li et al., 2015), aggression (Wong et al., 2016), contextual memory (Besnard et al., 2019; Jarrard, 1993; Leutgeb and Mizumori, 2002; Vouimba et al., 1998), food intake (Azevedo et al., 2019; Scopinho et al., 2008; Sweeney and Yang, 2015, 2016; Terrill et al., 2016), spatial memory (Jaffard et al., 1996; Simon et al., 1986), sexual behavior (Tsukahara et al., 2014), sexually dimorphic social play (Veenema et al., 2013), social preference (Shin et al., 2018), social memory (Leroy et al., 2018; Lukas et al., 2013), reward and addiction (Cornish et al., 2012; Heath, 1963; Luo et al., 2011; McGlinchey and Aston-Jones, 2018; Le Merrer et al., 2007; Olds and Milner, 1954; Sartor and Aston-Jones, 2012; Zahm et al., 2010), gastric motility (Gong et al., 2013), and endocrine responses to stress (Anthony et al., 2014; Usher et al., 1974; Yadin and Thomas, 1996). It remains to be seen whether multiple descending circuits operate in parallel, each with a unique behavioral function, or whether the behavioral phenotypes observed with LS manipulation are aspects of a single corticofugal computation.
The mnemonic functions of hippocampal sharp wave ripples (SPW-Rs) have been studied extensively. Because hippocampal outputs affect not only cortical but also subcortical targets, we examined the impact of SPW-Rs on the firing patterns of lateral septal (LS) neurons in behaving rats. A large fraction of SPW-Rs were temporally locked to high-frequency oscillations (HFOs) (120–180 Hz) in LS, with strongest coupling during non-rapid eye movement (NREM) sleep, followed by waking immobility. However, coherence and spike-local field potential (LFP) coupling between the two structures were low, suggesting that HFOs are generated locally within the LS GABAergic population. This hypothesis was supported by optogenetic induction of HFOs in LS. Spiking of LS neurons was largely independent of the sequential order of spiking in SPW-Rs but instead correlated with the magnitude of excitatory synchrony of the hippocampal output. Thus, LS is strongly activated by SPW-Rs and may convey hippocampal population events to its hypothalamic and brainstem targets.
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The focus of this study was a subset of neurons within a single brainstem nucleus, therefore its generalizability to higher level questions of consciousness systems should be tempered. However, while the present study taken in isolation is limited in scope with regards to mechanisms of consciousness, it builds on prior work showing a consistent link between states of conscious arousal and acetylcholine, the PPT and possible thalamic targets of the PPT (Feng et al., 2017; Furman et al., 2015; Li et al., 2015; Motelow et al., 2015). Postsynaptic hyperpolarization of a neuron could be caused by active inhibition, such as through GABAergic input opening chloride channels.
Focal limbic seizures often impair consciousness/awareness with major negative impact on quality of life. Recent work has shown that limbic seizures depress brainstem arousal systems, including reduced action potential firing in a key node: cholinergic neurons of the pedunculopontine tegmental nucleus (PPT). In vivo whole-cell recordings have not previously been achieved in PPT, but are used here with the goal of elucidating the mechanisms of reduced PPT cholinergic neuronal activity. An established model of focal limbic seizures was used in rats following brief hippocampal stimulation under light anesthesia. Whole-cell in vivo recordings were obtained from PPT neurons using custom-fabricated 9–10 mm tapered patch pipettes, and cholinergic neurons were identified histologically. Average membrane potential, input resistance, membrane potential fluctuations and variance were analyzed during seizures. A subset of PPT neurons exhibited reduced firing and hyperpolarization during seizures and stained positive for choline acetyltransferase. These PPT neurons showed a mean membrane potential hyperpolarization of −3.82 mV (±0.81 SEM, P < .05) during seizures, and also showed significantly increased input resistance, fewer excitatory post-synaptic potential (EPSP)-like events (P < .05), and reduced membrane potential variance (P < .01). The combination of increased input resistance, decreased EPSP-like events and decreased variance weigh against active ictal inhibition and support withdrawal of excitatory input as the dominant mechanism of decreased activity of cholinergic neurons in the PPT. Further identifying synaptic mechanisms of depressed arousal during seizures may lead to new treatments to improve ictal and postictal cognition.
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Epilepsy is characterized by recurrent seizures. Certain seizure types cause dysregulation of arousal and conscious awareness, whereas others relatively spare those impairments. Prior studies suggest that whether impaired consciousness is present or not during seizures largely depends on whether affected areas include cortical and subcortical regions that regulate consciousness. In absence epilepsy and temporal lobe epilepsy, consciousness impairments have been relatively well studied. Accordingly, we will discuss cellular and circuit mechanisms underlying dysregulation of consciousness in those types of epilepsies. Mechanistically, normal coordinated network activity (e.g., gamma oscillations) plays a key role in maintaining consciousness, whereas abnormal network activity in epilepsy (e.g., 3- to 4-Hz spike-and-wave discharges in absence seizures) is thought to be closely associated with dysregulation of consciousness. Thus, we will stress coordinated network activity in conjunction with its critical role in normal consciousness and dysregulation of consciousness in epilepsy. Finally, we will consider treatment strategies for dysregulation of consciousness in epilepsy and future directions.

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: This work was supported by National Institutes of Health R01 NS066974, R21 NS083783, the Swebelius Fund, and the Betsy and Jonathan Blattmachr Family (HB); National Institutes of Health P30 NS052519 (FH); National Institutes of Health F30 NS071628 and MSTP TG T32GM07205 (JEM), a China Scholarship Council Postgraduate Scholarship Program award CSC 201206190071 (WL); and a China Scholarship Council Postgraduate Scholarship Program award CSC 201206370075 (QZ).

: Conflict of interest: The authors declare no competing financial interests.

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Deep Brain Stimulation (DBS)Original ArticleCortical Network Switching: Possible Role of the Lateral Septum and Cholinergic Arousal

Highlights

Abstract

Background

Hypothesis

Methods and results

Conclusions

Introduction

Section snippets

Animal preparation, surgery and histology

Lateral septal stimulation and toe pinch cause reciprocal changes in cortical delta power

Discussion

Acknowledgments

Lancet Neurol

Epilepsy Behav

Prog Brain Res

Brain Res

Brain Res Brain Res Rev

J Neurosci Methods

Pharmacol Biochem Behav

The human brain is intrinsically organized into dynamic, anticorrelated functional networks

Proc Natl Acad Sci U S A

A putative flip-flop switch for control of REM sleep

Nature

Cholinergic and noradrenergic modulation of the slow (approximately 0.3 Hz) oscillation in neocortical cells

J Neurophysiol

Ictal neocortical slowing in temporal lobe epilepsy

Neurology

Impaired consciousness in temporal lobe seizures: role of cortical slow activity

Brain

Remote effects of focal hippocampal seizures on the rat neocortex

J Neurosci

Cortical deactivation induced by subcortical network dysfunction in limbic seizures

J Neurosci

Gamma-aminobutyric acid-mediated neurotransmission in the pontine reticular formation modulates hypnosis, immobility, and breathing during isoflurane anesthesia

Anesthesiology

Initiation of epileptiform activity by excitatory amino acid receptors in the disinhibited rat neocortex

J Neurophysiol

Septo-hippocampal networks in chronically epileptic rats: potential antiepileptic effects of theta rhythm generation

J Neurophysiol

Afferent connections of the substantia innominata/basal nucleus of Meynert in carnivores and primates

J Hirnforsch

Deep Brain Stimulation (DBS)
Original Article
Cortical Network Switching: Possible Role of the Lateral Septum and Cholinergic Arousal