Increases of Phospho-Tau (Ser202/Thr205) in the Olfactory Regions Are Associated With Impaired EEG and Olfactory Behavior in Traumatic Brain Injury Mice

Traumatic brain injury (TBI) leads to long-term cognitive impairments with an increased risk for neurodegenerative and psychiatric disorders. Among these various impairments, olfactory dysfunction is one of the most common symptoms in TBI patients. However, there are very few studies that show the association between olfactory dysfunction and repetitive TBI, which accounts for the majority of all head injuries. In this present study, we investigated the effects of repetitive TBI on olfactory functioning and the related pathological neuronal injuries in mice. Through pathological examination, we found a significant increase in p-Tau (S202/T205) in olfactory bulb-associated areas such as the Anterior Olfactory Nucleus (AON), Pyriform Cortex (PC), Tenia Tecta (TT), and Olfactory Tubercle (OT). Neuronal atrophy in the Lateral Anterior Olfactory Nucleus (AOL), Granule Layer Olfactory Bulb (GrO), and Dorsal Tenia Tecta (DTT) was also found to be correlated with p-Tau levels. Furthermore, electroencephalography (EEG) of repetitive TBI mouse models showed impaired spontaneous delta oscillation, as well as altered cross-frequency coupling between delta phase and amplitudes of the fast oscillations in the resting-state olfactory bulb. Also, abnormal alterations in EEG band powers were observed during the olfactory oddball paradigm test. This study provides evidence of pathological and physiological alterations in the mouse olfactory system caused by repetitive TBI. Together, p-Tau alterations and EEG impairments may serve as important biomarkers of olfactory track-associated dysfunctions and behavioral impairments commonly observed in repetitive TBI patients.

Increases of phospho-Tau (Ser202/Thr205) in the olfactory regions are associated with impaired EEG and olfactory behavior in traumatic brain injury mice

Traumatic brain injury (TBI) leads to long-term cognitive impairments with an increased risk for neurodegenerative and psychiatric disorders. Among these various impairments, olfactory dysfunction is one of the most common symptoms in TBI patients. However, there are very few studies that show the association between olfactory dysfunction and repetitive TBI, which accounts for the majority of all head injuries. In this present study, we investigated the effects of repetitive TBI on olfactory functioning and the related pathological neuronal injuries in mice. Through pathological examination, we found a significant increase in p-Tau (S202/T205) in olfactory bulb-associated areas such as the Anterior Olfactory Nucleus (AON), Pyriform Cortex (PC), Tenia Tecta (TT), and Olfactory Tubercle (OT). Neuronal atrophy in the Lateral Anterior Olfactory Nucleus (AOL), Granule Layer Olfactory Bulb (GrO), and Dorsal Tenia Tecta (DTT) was also found to be correlated with p-Tau levels. Furthermore, electroencephalography (EEG) of repetitive TBI mouse models showed impaired spontaneous delta oscillation, as well as altered cross-frequency coupling between delta phase and amplitudes of the fast oscillations in the resting-state olfactory bulb. Also, abnormal alterations in EEG band powers were observed during the olfactory oddball paradigm test. This study provides evidence of pathological and physiological alterations in the mouse olfactory system caused by repetitive TBI. Together, p-Tau alterations and EEG impairments may serve as important biomarkers of olfactory track-associated dysfunctions and behavioral impairments commonly observed in repetitive TBI patients.

Dynamic inhibition of sensory responses mediated by an olfactory corticofugal system

Processing of sensory information is substantially modulated by centrifugal projections from higher cortical areas, yet their behavioral relevance and underlying neural mechanisms remain unclear in most cases. The anterior olfactory nucleus (AON) is part of the olfactory cortex and its extensive connections to lower and higher brain centers put it in a prime position to modulate early sensory information in the olfactory system. Here, we show that optogenetic activation of AON neurons in awake animals was not perceived as an odorant equivalent cue. However, AON activation during odorant presentation reliably suppressed odor responses. This AON mediated effect was fast and constant across odors and concentrations. Likewise, activation of glutamatergic AON projections to the olfactory bulb (OB) transiently inhibited the excitability of mitral/tufted cells (MTCs) that relay olfactory input to cortex. Single-unit MTC recordings revealed that optogenetic activation of glutamatergic AON terminals in the OB transiently decreased sensory-evoked MTC spiking, regardless of the strength or polarity of the sensory response. These findings suggest that glutamatergic AON projections to the OB suppress early olfactory processing by inhibiting OB output neurons and that the AON can dynamically gate sensory throughput to the cortex.Significance StatementThe anterior olfactory nucleus (AON) as an olfactory information processing area sends extensive projections to lower and higher brain centers but the behavioral consequences of its activation have been scarcely investigated. Using behavioral tests in combination with optogenetic manipulation we show that in contrast to what has been suggested previously, the AON does not seem to form odor percepts but instead suppresses odor responses across odorants and concentrations. Furthermore, this study shows that glutamatergic cortical projections to the olfactory bulb suppress olfactory processing by inhibiting output neurons, pointing to a potential mechanisms by which the olfactory cortex can actively and dynamically gate sensory throughput to higher brain centers.HighlightsAON stimulation suppresses odor responses across odorants and concentrationsAON activation is not perceived as an odorant equivalent cueThe AON dynamically shapes olfactory bulb output on a fast timescaleAON input to the olfactory bulb strongly suppresses mitral/tufted cells firing

Deficits in olfactory sensitivity in a mouse model of Parkinson’s disease revealed by plethysmography of odor-evoked sniffing

Hyposmia is evident in over 90% of Parkinson’s disease (PD) patients. A characteristic of PD is intraneuronal deposits composed in part of α-synuclein fibrils. Based on the analysis of post-mortem PD patients, Braak and colleagues suggested that early in the disease α-synuclein pathology is present in the dorsal motor nucleus of the vagus, as well as the olfactory bulb and the anterior olfactory nucleus, and then later affects other interconnected brain regions. Here, we bilaterally injected α-synuclein preformed fibrils into the olfactory bulb of wild type male and female mice. Six-months after injection, the anterior olfactory nucleus and the piriform cortex displayed a high α-synuclein pathology load. We evaluated olfactory perceptual function by monitoring odor-evoked sniffing behavior in a plethysmograph at one-, three- and six-months after injection of α-synuclein fibrils. At all-time points, females injected with fibrils exhibited reduced odor detection sensitivity, which was detectable with the semi-automated plethysmography apparatus, but not a buried pellet test. In future studies, this sensitive methodology we used to assess olfactory detection deficits could be used to define how α-synuclein pathology affects other aspects of olfactory perception in PD models and to clarify the neuropathological underpinnings of these deficits.Highlights- α-synuclein pathology spreads through neuronally-connected areas after bilateral injection of preformed fibrils into the olfactory bulb.- A plethysmograph and an olfactometer were used for a semi-automated screen of odor-evoked sniffing as an assay for odor detection sensitivity.- Bilateral olfactory bulb injections of α-synuclein preformed fibrils in female mice led to reduced sensitivity for detecting odors.- The semi-automated plethysmography apparatus was more sensitive at detecting odor detection deficits than the buried pellet test.