A New Projection From the Deep Cerebellar Nuclei to the Hippocampus via the Ventrolateral and Laterodorsal Thalamus in Mice

Bohne, Pauline; Schwarz, Martin K.; Herlitze, Stefan; Mark, Melanie D.

doi:10.3389/fncir.2019.00051

Cited by 74 publications

(81 citation statements)

References 73 publications

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“…; Bohne et al . ), and we see no fibres from fastigial neurons in the hippocampus in our virally injected animals (data not shown). This suggests that other downstream pathways engaged by cerebellar stimulation must underlie hippocampal seizure attenuation (for a review, see Yu & Krook‐Magnuson, ).…”

Section: Discussionmentioning

confidence: 63%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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Key pointsr On-demand optogenetic inhibition of glutamatergic neurons in the fastigial nucleus of the cerebellum does not alter hippocampal seizures in a mouse model of temporal lobe epilepsy.r In contrast, on-demand optogenetic excitation of glutamatergic neurons in the fastigial nucleus successfully inhibits hippocampal seizures. With this approach, even a single 50 ms pulse of light is able to significantly inhibit seizures.r On-demand optogenetic excitation of glutamatergic fastigial neurons either ipsilateral or contralateral to the seizure focus is able to inhibit seizures.r Selective excitation of glutamatergic nuclear neurons provides greater seizure inhibition than broadly exciting nuclear neurons without cell-type specificity.Abstract Temporal lobe epilepsy is the most common form of epilepsy in adults, but current treatment options provide limited efficacy, leaving as many as one-third of patients with uncontrolled seizures. Recently, attention has shifted towards more closed-loop therapies for seizure control, and on-demand optogenetic modulation of the cerebellar cortex was shown to be highly effective at attenuating hippocampal seizures. Intriguingly, both optogenetic excitation and inhibition of cerebellar cortical output neurons, Purkinje cells, attenuated seizures. The mechanisms by which the cerebellum impacts seizures, however, are unknown. In the present study, we targeted the immediate downstream projection of vermal Purkinje cells -the fastigial nucleus -in order to determine whether increases and/or decreases in fastigial output can underlie seizure cessation. Though Purkinje cell input to fastigial neurons is inhibitory, direct optogenetic inhibition of the fastigial nucleus had no effect on seizure duration. Conversely, however, fastigial excitation robustly attenuated hippocampal seizures. Seizure cessation was achieved at multiple stimulation frequencies, regardless of laterality relative to seizure focus, and even with single light pulses. Seizure inhibition was greater when selectively targeting glutamatergic fastigial neurons than when an approach that lacked cell-type specificity was used. Together, these results suggest Martha Streng received a BA in Neuroscience and Behaviour from Mount Holyoke College and a PhD in Neuroscience from the University of Minnesota, Twin Cities, where she studied the encoding of motor predictive and feedback information by Purkinje cells during online motor control tasks. Her current research focuses on the characterization of cerebellar circuitry and output channels in health and disease. that stimulating excitatory neurons in the fastigial nucleus may be a promising approach for therapeutic intervention in temporal lobe epilepsy.

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Section: Discussionmentioning

confidence: 63%

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Streng

Krook-Magnuson

2019

The Journal of Physiology

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“…This is in contrast with the traditional view associating the cerebellum exclusively with motor coordination and learning, but supported by more recent studies, which have revealed a role for the cerebellum in cognitive functions such as attention, language, working memory, emotion, and in visuospatial navigation (Timmann and Daum, 2007;Baillieux et al, 2008;Timmann et al, 2010). Viral tracer studies have recently demonstrated previously unknown connections between the cerebellum and hippocampus -in particular a polysynaptic circuit from the cerebellar fastigial nucleus with a thalamic relay in the LDDM/LDVL and VL, which in turn synapses on the subiculum, retrosplenial cortex, and rhinal cortex, which all project to the hippocampus (Bohne et al, 2019). These connections are indicative of a role in spatial navigation.…”

Section: Discussionmentioning

confidence: 99%

Identifying Vulnerable Brain Networks in Mouse Models of Genetic Risk Factors for Late Onset Alzheimer’s Disease

Badea

Shuff

et al. 2019

Front. Neuroinform.

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The major genetic risk for late onset Alzheimer's disease has been associated with the presence of APOE4 alleles. However, the impact of different APOE alleles on the brain aging trajectory, and how they interact with the brain local environment in a sex specific manner is not entirely clear. We sought to identify vulnerable brain circuits in novel mouse models with homozygous targeted replacement of the mouse ApoE gene with either human APOE3 or APOE4 gene alleles. These genes are expressed in mice that also model the human immune response to age and disease-associated challenges by expressing the human NOS2 gene in place of the mouse mNos2 gene. These mice had impaired learning and memory when assessed with the Morris water maze (MWM) and novel object recognition (NOR) tests. Ex vivo MRI-DTI analyses revealed global and local atrophy, and areas of reduced fractional anisotropy (FA). Using tensor network principal component analyses for structural connectomes, we inferred the pairwise connections which best separate APOE4 from APOE3 carriers. These involved primarily interhemispheric connections among regions of olfactory areas, the hippocampus, and the cerebellum. Our results also suggest that pairwise connections may be subdivided and clustered spatially to reveal local changes on a finer scale. These analyses revealed not just genotype, but also sex specific differences. Identifying vulnerable networks may provide targets for interventions, and a means to stratify patients.

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“…Specifically, the basolateral amygdaloid complex (BLA) integrates information regarding fear and anxiety-inducing stimuli, regulating emotional and behavioral responses ( 20 ). Furthermore, the BLA receives sensory information, such as vestibular outputs, through axons networking through the superior and lateral vestibular nuclei, which then project through the thalamic nuclei to the BLA ( 21 ). Evidence linking pathological dysfunction of the amygdala and thalamus to sensory impairments is important to further understanding the mechanisms associated with bTBI.…”

Section: Introductionmentioning

confidence: 99%

Glial Activation in the Thalamus Contributes to Vestibulomotor Deficits Following Blast-Induced Neurotrauma

et al. 2020

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Vestibular impairment has become a frequent consequence following blast-related traumatic brain injury (bTBI) in military personnel and Veterans. Behavioral outcomes such as depression, fear and anxiety are also common comorbidities of bTBI. To accelerate pre-clinical research and therapy developments, there is a need to study the link between behavioral patterns and neuropathology. The transmission of neurosensory information often involves a pathway from the cerebral cortex to the thalamus, and the thalamus serves crucial integrative functions within vestibular processing. Pathways from the thalamus also connect with the amygdala, suggesting thalamic and amygdalar contributions to anxiolytic behavior. Here we used behavioral assays and immunohistochemistry to determine the sub-acute and early chronic effects of repeated blast exposure on the thalamic and amygdala nuclei. Behavioral results indicated vestibulomotor deficits at 1 and 3 weeks following repeated blast events. Anxiety-like behavior assessments depicted trending increases in the blast group. Astrogliosis and microglia activation were observed upon post-mortem pathological examination in the thalamic region, along with a limited glia response in the amygdala at 4 weeks. These findings are consistent with a diffuse glia response associated with bTBI and support the premise that dysfunction within the thalamic nuclei following repeated blast exposures contribute to vestibulomotor impairment.

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A New Projection From the Deep Cerebellar Nuclei to the Hippocampus via the Ventrolateral and Laterodorsal Thalamus in Mice

Cited by 74 publications

References 73 publications

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Excitation, but not inhibition, of the fastigial nucleus provides powerful control over temporal lobe seizures

Identifying Vulnerable Brain Networks in Mouse Models of Genetic Risk Factors for Late Onset Alzheimer’s Disease

Glial Activation in the Thalamus Contributes to Vestibulomotor Deficits Following Blast-Induced Neurotrauma

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