Scientific Understanding of Consciousness
Gamma Oscillations and Cellular Pathologies
Nature 540, 230–235 (08 December 2016)
Gamma frequency entrainment attenuates amyloid load and modifies microglia
Hannah F. Iaccarino, et.al.
Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.,
McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
MIT Media Lab, Departments of Biological Engineering and Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
Institute of Medical Engineering and Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,
Massachusetts General Hospital, Boston, Massachusetts, Massachusetts 02114, USA,
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02139, USA.
Changes in gamma oscillations (20–50 Hz) have been observed in several neurological disorders. However, the relationship between gamma oscillations and cellular pathologies is unclear. Here we show reduced, behaviourally driven gamma oscillations before the onset of plaque formation or cognitive decline in a mouse model of Alzheimer’s disease. Optogenetically driving fast-spiking parvalbumin-positive (FS-PV)-interneurons at gamma (40 Hz), but not other frequencies, reduces levels of amyloid-β (Aβ)1–40 and Aβ 1–42 isoforms. Gene expression profiling revealed induction of genes associated with morphological transformation of microglia, and histological analysis confirmed increased microglia co-localization with Aβ. Subsequently, we designed a non-invasive 40 Hz light-flickering regime that reduced Aβ1–40 and Aβ1–42 levels in the visual cortex of pre-depositing mice and mitigated plaque load in aged, depositing mice. Our findings uncover a previously unappreciated function of gamma rhythms in recruiting both neuronal and glial responses to attenuate Alzheimer’s-disease-associated pathology.
Activation of local circuits of excitatory and fast-spiking inhibitory neurons that resonate at 20–50 Hz gives rise to oscillations in the local field potential (LFP), called gamma oscillations. Although studies have demonstrated disrupted gamma in various neurological diseases, the interplay between pathology and this emergent circuit property has yet to be determined. In general, molecular and cellular pathology is thought to alter synaptic activity. However, in at least one disorder, Alzheimer’s disease (AD), changes in synaptic activity can also feedback to alter molecular pathology. Studies have shown that increases in synaptic activity in vivo increase levels of Aβ6, a 36- to 43-amino-acid protein, whose aggregation is thought to initiate neurotoxic events, including neuroinflammation, synaptic and neuronal loss, and tau-associated pathology. We aimed to determine how gamma affects molecular pathology in a mouse model of AD. Understanding how gamma might affect disease pathogenesis has important implications for elucidating both the basic pathology of and possible therapeutic interventions for neurological diseases with altered gamma.
Altered gamma has been observed in multiple brain regions in several neurological and psychiatric disorders, including a reduction in spontaneous gamma synchronization in patients with AD and reduced gamma power in multiple AD mouse models. However, it is unclear whether gamma is altered early in disease progression and whether it affects disease pathology. Accordingly, we recorded neural activity from behaving 5XFAD mice, a well-established model of AD. In 3-month-old mice, which have elevated levels of Aβ but no major plaque accumulation in the hippocampus or manifestation of learning and memory deficits, we recorded neural activity from hippocampal subregion CA1, where gamma has been particularly well characterized using a virtual environment. In CA1, gamma is present during distinct periods of activity: running, when theta oscillations (4–12 Hz) occur, and quiescent behaviour, when sharp-wave ripples (SWRs) occur. We found no clear differences in slow gamma power (20–50 Hz) between 5XFAD mice and wild-type (WT) littermates during theta.
Gamma oscillations are thought to be important for higher cognitive functions and sensory responses. Here, we demonstrated that entraining oscillations and spiking at 40 Hz, using optogenetics in the hippocampus of 5XFAD mice and using a non-invasive light flicker treatment to affect primary VC in multiple mouse models, resulted in a marked reduction of Aβ peptides. We also found a concomitant microglia response after 40 Hz entrainment.
The robust reduction of total amyloid levels was probably mediated both by decreased amyloidogenesis and by increased amyloid endocytosis by microglia. Thus, it appears that driving 40 Hz gamma oscillations may induce an overall neuroprotective response that recruits both neurons and microglia. The fact that GABAA antagonist treatment completely abrogated the effects of 40 Hz stimulation on Aβ levels strongly suggests that GABAergic neurotransmission is critical for these effects.
Flicker stimulation at 40 Hz reduced Aβ in multiple mouse models, including 5XFAD, APP/PS1, and WT mice. This replication in multiple mouse models shows that these findings are not specific to one animal model and, importantly, extend to situations where Aβ is produced from APP expressed by its physiological promoter as it is in WT animals. In addition, we found that 40 Hz oscillations reduced phosphorylated tau staining in a mouse model of tauopathy, TauP301S, showing that the protective effects of gamma stimulation generalize to other pathogenic proteins.
These observations indicate that entraining gamma oscillations may provide a broad spectrum of systemic effects in the brain, including in non-neuronal cells, to attenuate AD-related pathology. Because this approach is fundamentally different from previous AD therapies, further study is needed to determine whether it will be therapeutic in human AD.
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