Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders: EEG approach expectations

Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders: EEG approach expectations

An imbalance between activities of different structures and neurotransmitter systems in the brain is suggested to be the main cause of its abnormal functioning in neurodegenerative pathologies. Electroencephalogram (EEG) registered from areas speci fi cally linked with a disease in combination with pharma‐cological testing of involved mediatory systems allows discovery of its progression and mechanism(s).is, in turn, potentiates development of perspective approaches for early diagnostic and e ff ective treatment of neurodegenerative disorders.

The neurodegenerative disorders are characterized by pro‐nounced disturbances in the brain functioning, which are asso‐ciated with considerable damage or destruction of the cerebral cells and/or connections between them. The most prominent effects of the neurodegeneration are observed when it affects the main neurotransmitter systems in the brain: dopaminergic (DA), cholinergic (ACh), γ‐aminobutyric acid (GABA), and glutamatergic (Glu). In Parkinson’s disease (PD), Alzheimer’s disease (AD), and temporal lobe epilepsy (TLE), close associ‐ations with disturbances in these systems were revealed (see,e.g.,1993, 265:1001;Neuropharmacology2013, 64:108;Front Aging Neurosci2014, 25:252;Brain Res Mol Brain Res2003, 113:107;Neuropharmacology1992, 31:469). On the other hand, the brain areas/structures involved in the mechanisms of learning/memory, attention and locomotion (the hippocampus, cortex, and basal ganglia) are well known to be specifically sensitive to detrimental influence of the neurode‐generation on the neurotransmitter systems as well (Xu et al., 2012). An imbalance between functional/electrical activities of di ff erent brain structures and their synchronized interaction is hypothesized to be the main cause of abnormal functioning of the diseased brain because of failed computation across neuro‐nal populations (Oswal et al., 2013). To clarify this, we analyzed the frequency composition of EEG registered from those brain areas which have been expected to be predominantly su ff ered from neurodegeneration in rat models of PD, AD, and TLE.e main objectives were associated with revelation of both imbal‐anced interplay between these areas and disturbances in their neurotransmitter mediation.

In patients with AD, alterations in the brain EEG asymme‐try and de fi cits in interhemispheric integration of information are well known. However, no direct evidence of an associa‐tion between EEG asymmetry, morphological markers in the brain, and cognition was found either in AD patients or in AD models. To clarify this, we performed experiments in rats with preliminarily removed olfactory bulbs (OBX rats), as a model of AD (Bobkova et al., 2008). We tested both learning/memory ability of OBX rats, amyloid‐beta peptides (Aβ) level (as an AD marker) in their brains, and EEG frequency spectra (0.5–30 Hz) in symmetrical frontal and occipital cortices. Close associations between impaired memory, increased Aβ in the cortex‐hip‐pocampus samples, and both eliminated beta rhythms (14–30 Hz) and enhanced theta oscillations (4‐8 Hz) in the right fron‐ tal cortex were revealed in OBX rats. These contrasted with non‐specific effects in the occipital brain areas, corroborating well‐known role of frontal cortex in mental processing. Given the data pointing at involvement of ACh system in both AD and EEG asymmetry in frontal cortex of naïve rats (Vorobyov and Ahmetova, 1998), the EEG approach might be considered as a potentially e ff ective tool for analysis of the brain neurotransmit‐ter and compensatory/adaptive mechanisms in AD progression (Bobkova and Vorobyov, 2015).

Microinjections of Aβ peptides into the hippocampus allow investigation of their direct effects on the brain, revealing, in turn, symptomatic and pathophysiological similarities of this model to AD. Recently, we have studied di ff erences in frequen‐cy spectra of EEG from frontal cortex and dorsal hippocampus (the main brain areas involved in learning/memory mecha‐nisms) in rats intrahippocampally infused with Aβ1—42(Vorobyov et al., 2015). Two weeks aer Aβ1—42injection, predominance of both hippocampal theta and cortical beta, observed in baseline EEG of control rats, was signi fi cantly diminished. DA has been shown to be involved in neuronal plasticity and Aβ transfor‐mation in different ways. To clarify DA involvement in the cortex‐hippocampus interplay in Aβ model of AD, we used pe‐ripheral injection of a DA agonist, apomorphine (APO). In rats infused with Aβ1–42alone, APO attenuated the cortical beta pre‐dominance. Interestingly, pretreatment (30 minutes apart) with dispersed fullerene C60nanoparticles, namely hydrated fullerene C60(C60HyFn), protected the intracerebral interplay from Aβ1–42detrimental in fl uence on both baseline EEG and APO‐produced EEG e ff ects.ese correlated with results of morphological and histochemical evaluation of neuronal viability in the hippo‐campus. We suggested that presynaptic DA mediation plays an important role in the C60HyF e ff ects and that C60HyF has neu‐roprotective potential in the Aβ model of AD (Vorobyov et al., 2015).

Some movement disorders in patients with PD have been suggested to be associated with an imbalance between cortical and striatal network activities with several frequency modes of oscillation (Mov Disorder2003,18:357).is imbalance is sup‐posedly linked with the brain DA level depletion and reversed by treatment either with APO or with traditionally used DA precursor, L‐DOPA. In the 6‐hydroxydopamine (6‐OHDA) rat model of PD, we studied the frequency spectra of EEG from frontal cortex and the striatum before and aer injection of APO alone or in combination with the NMDA antagonist, MK‐801 (Vorobyov et al., 2003; Vorobyov and Sengpiel, 2008). 6‐OHDA intoxication produced disparity in baseline EEG spec‐tra through both suppressed striatal alpha (7.6–12.5 Hz) and enhanced cortical beta. In control rats, APO evoked long‐last‐ing suppression of alpha activity, predominantly in the cortex, whereas in 6‐OHDA rats, even larger suppressive e ff ect was ob‐served in the beta range, again signi fi cantly more pronounced in the cortex than in the striatum. In 6‐OHDA rats, pretreatment with MK‐801 eliminated the APO‐induced cortex‐striatum dif‐ference in the beta range, inversed the e ff ect in the alpha range, and intensi fi ed delta activity (0.5–3.5 Hz) stronger in the stria‐tum than in the cortex. We conclude that frequency‐dependent di ff erences in EEG power between the cortex and striatum may be involved in DA treatment of PD and mediated, at least in part, through NMDA receptors (Vorobyov and Sengpiel, 2008). Furthermore, we evaluated DA receptors sensitization provoked by repetitive APO injections, which is considered as a basis of the complications observed in chronic treatment of PD by DA agonists. To study this so‐called “priming” phenomenon, we used speci fi c D1agonist, SKF 38393, on the third day aer APO (Vorobyov et al., 2003). In 6‐OHDA‐lesioned rats, SKF 38393decreased beta1(12.6–17.5 Hz) activities in both the cortex and the striatum. The effect of SKF 38393 was enhanced in APO‐primed rats pretreated with MK‐801, particularly in the stria‐tum. We suggest that long‐term changes in cortical‐striatal EEG interplay aer priming might contribute to the development of the behavioral complications observed in chronic treatment of PD with DA agonists.

Experiments on kainic acid (KA)‐injected rodents, as a model of TLE, have demonstrated that the neuronal circuit‐ries of the cortex and the hippocampus as well as the major neurotransmitter systems undergo fundamental degenerative modifications (see,e.g., Buckmaster and Dudek, 1997;Brain Res1980, 191:387;Brain Res Mol Brain Res2003, 113:107;Neuropharmacology1992, 31:469). To clarify the extent of di ff erent neurotransmitter systems involvement in epilepsy‐associated alterations in the brain, we recorded EEG from the cortex and hippocampus before and after intracerebroventricular (i.c.v.) infusions of agonists at NMDA, α2‐adrenegic, GABAa, and GABAbreceptors (NMDA, clonidine, muscimol, and baclofen, respectively) in rats intraperitoneally injected with KA. Since the development of KA‐induced TLE is known to comprise acute, delayed, and chronic stages of neurodegeneration and compensatory remodeling, EEG e ff ects of the neurotransmitters were studied 2, 5, and 9 weeks after KA injection alone or in combination with basic fi broblast growth factor (bFGF, i.c.v.), used as a neuroprotective agent (Vorobyov et al., 2005). Within the first 5 weeks of KA injection, the EEG power shifted to‐wards the lower frequency range, the EEG responses to NMDA and clonidine were potentiated, whereas the e ff ects mediated by GABAaand GABAbreceptors remained largely unaffected. In KA rats, bFGF potently mitigated abnormally increased NMDA sensitivity.us, we have showed how the neuroprotective ac‐tion of bFGF, and its bene fi cial e ff ects on subsequent neuronal and mediatory systems remodeling, are re fl ected in frequency spectra of the brain activity.

We developed this approach in our further study associated with analysis of mediatory mechanisms underlying well‐known“bidirectional” relationship between attention‐deficit hyper‐activity disorder (ADHD) and epilepsy (see,e.g., Hamoda et al., 2009). In spontaneously hypertensive (SH) rats, as a model of ADHD, the baseline EEG showed increased delta and beta2activity (17.8–26.5 Hz) in the hippocampus and decreased al‐pha‐beta1activity in both the hippocampus and frontal cortex (Vorobyov et al., 2011). In KA rats, these e ff ects were observed 2 weeks after KA injection, while the beta2activity increase occurred aer 5 weeks in the hippocampus and, largely, aer 9 weeks in both brain areas. In SH rats, NMDA increased del‐ta and decreased alpha‐beta1activity, similar to KA rats aer five post‐injection weeks. In SH rats, clonidine augmented theta‐beta2increase in the cortex and alpha suppression in both brain areas, in parallel with induction of beta2activity in the hippocampus. These beta2effects were observed 5 and 9 weeks aer KA injection. In SH rats, baclofen produced robust delta‐theta enhancement and alpha‐beta1suppression in both brain areas, with additional beta2activity increase in the hip‐pocampus, while muscimol was ine ff ective in both groups of rats. In KA rats, EEG responses to GABA agonists were similar to those in control. Our results demonstrate sensitization of NMDA receptors and alpha2‐adrenoceptors in SH and KA rats, and that of GABAbreceptors speci fi cally in SH rats.

Grant RFBR 16-04-00942 (Russia) to NB: “A study of the brain dopaminergic system involvement in mechanisms of Alzheimer’s disease on models of its sporadic and inherited types”.

Vasily Vorobyov＊, Natalia Bobkova

Institute of Cell Biophysics, Russian Academy of Sciences, Moscow Region, Russia

＊Correspondence to: Vasily Vorobyov, Ph.D., vorobyovv2@gmail.com.

Accepted:2016-12-30

orcid: 0000-0002-7716-2580 (Vasily Vorobyov)

Bobkova N, Vorobyov V (2015) The brain compensatory mechanisms and Alzheimer’s disease progression: a new protective strategy. Neural Regen Res 10:696‐697.

Bobkova N, Vorobyov V, Medvinskaya N, Aleksandrova I, Nesterova I (2008) Interhemispheric EEG di ff erences in olfactory bulbectomized rats with dif‐ferent cognitive abilities and brain beta‐amyloid levels. Brain Res 1232:185‐194.

Buckmaster PS, Dudek FE (1997) Neuron loss, granule cell axon reorganiza‐tion, and functional changes in the dentate gyrus of epileptic kainate‐treat‐ed rats. J Comp Neurol 385:385‐404.

Hamoda HM, Guild DJ, Gumlak S, Travers BH, Gonzalez‐Heydrich J (2009) Association between attention‐de fi cit/hyperactivity disorder and epilepsy in pediatric populations. Expert Rev Neurother 9:1747‐1754.

Oswal A, Brown P, Litvak V (2013) Synchronized neural oscillations and the pathophysiology of Parkinson’s disease. Curr Opin Neurol 26:662‐670.

Vorobyov VV, Ahmetova ER (1998) Muscarinic elicitation of EEG asymmetry in freely moving rats. Brain Res 794:299‐303.

Vorobyov V, Kaptsov V, Gordon R, Makarova E, Podolski I, Sengpiel F (2015) Neuroprotective e ff ects of hydrated fullerene C60: cortical and hippocam‐pal EEG interplay in an amyloid‐infused rat model of Alzheimer’s disease. J Alzheimers Dis 45:217‐233.

Vorobyov V, Schibaev N, Kaptsov V, Kovalev G, Sengpiel F (2011) Cortical and hippocampal EEG effects of neurotransmitter agonists in sponta‐neously hypertensive vs. kainate‐treated rats. Brain Res 1383:154‐168.

Vorobyov V, Schibaev N, Kovalev G, Alzheimer C (2005) Effects of neu‐rotransmitter agonists on electrocortical activity in the rat kainate model of temporal lobe epilepsy and the modulatory action of basic fibroblast growth factor. Brain Res 1051:123‐136.

Vorobyov VV, Schibaev NV, Morelli M, Carta AR (2003) EEG modi fi cations in the cortex and striatum aer dopaminergic priming in the 6‐hydroxy‐dopamine rat model of Parkinson’s disease. Brain Res 972:177‐185.

Vorobyov V, Sengpiel F (2008) Apomorphine‐induced di ff erences in cortical and striatal EEG and their glutamatergic mediation in 6‐hydroxydopa‐mine‐treated rats. Exp Brain Res 191:277‐287.

Xu Y, Yan J, Zhou P, Li J, Gao H, Xia Y, Wang Q (2012) Neurotransmitter receptors and cognitive dysfunction in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 97:1‐13.

10.4103/1673-5374.198981

How to cite this article:Vorobyov V, Bobkova N (2017) Intracerebral interplay and neurotransmitter systems involvement in animal models of neurodegenerative disorders: EEG approach expectations. Neural Regen Res 12(1):66-67.

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