The Abelson-helper integration site 1 ( AHI1 ) gene encodes for a ciliary transition zone localizing protein that when mutated causes the human ciliopathy, Joubert syndrome. We prepared and examined neuronal cultures derived from male and female embryonic Ahi1 +/+ and Ahi1 -/- mice (littermates) and found that the distribution of ciliary MchR1 was significantly reduced in Ahi1 -/- neurons; however, the total and surface expression of MchR1 on Ahi1 -/- neurons was similar to controls ( Ahi1 +/+). This indicates that a pathway for MchR1 trafficking to the surface plasma membrane is intact, but the process of targeting MchR1 into cilia is impaired in Ahi1 deficient mouse neurons, indicating a role for Ahi1 in localizing MchR1 to the cilium. Mouse Ahi1 -/- neurons that fail to accumulate MchR1 in the ciliary membrane have significant decreases in two downstream MchR1 signaling pathways (cAMP and Erk) upon MCH stimulation. These results suggest that the ciliary localization of MchR1 is necessary and critical fo...

Dopaminergic (DA) neurons of the midbrain are involved in controlling animals’ orienting and approach toward relevant external stimuli. The firing of DA neurons is regulated by many brain structures; however, the sensory input is provided predominantly by the ipsilateral superior colliculus (SC). It is suggested that SC also innervates the contralateral rostromedial tegmental nucleus (RMTg)—the main inhibitory input to DA neurons. Therefore, this study aimed to describe the physiology and anatomy of the SC-RMTg pathway. To investigate the anatomical connections within the circuit of interest, anterograde, retrograde, and transsynaptic tract-tracing studies were performed on male Sprague-Dawley rats. We have observed that RMTg is monosynaptically innervated predominantly by the lateral parts of the intermediate layer of the contralateral SC. To study the physiology of this neuronal pathway, we conducted in vivo electrophysiological experiments combined with optogenetics; the activity of RMTg neurons was rec...

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicate that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aβ and Tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aβ production suffer from seizures and epilepsy prior to the development of plaques. Similarly, pathological accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aβ on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments. Significance statement Abnormal neuronal network excitability may lead to hypersynchrony, ...

The Stromal interaction molecule 1 (STIM1), is an ER-Ca2+ sensor and an essential component of ER-Ca2+ store operated Ca2+ entry (SOCE). Loss of STIM1 affects metabotropic Glutamate Receptor 1 (mGluR1) mediated synaptic transmission, neuronal Ca2+ homeostasis and intrinsic plasticity in Purkinje Neurons (PNs). Long-term changes of intracellular Ca2+ signaling in PNs lead to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca2+ channel, the Inositol 1,4,5-triphosphate receptor (IP3R). Here, we asked if changes in such intrinsic neuronal properties, due to loss of STIM1, have an age-dependent impact on PNs. Consequently, we analyzed mRNA expression profiles and cerebellar morphology in PN specific STIM1 knockout mice ( STIM1PKO ) of both sexes across ages. Our study identified a requirement for STIM1 mediated Ca2+ signaling in maintaining the expression of genes belonging to key biological networks of synaptic function and neurite development amongst others. Gene expression ch...

The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Utilizing a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2 adrenoreceptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto medium spiny projection neurons (MSNs) evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into...

Transcranial random noise stimulation (tRNS) over cortical areas has been shown to acutely improve performance in sensory detection tasks. One explanation for this behavioural effect is stochastic resonance, a mechanism that explains how signal processing in non-linear systems can benefit from added noise. While acute noise benefits of electrical random noise stimulation have been demonstrated at the behavioural level as well as in in vitro preparations of neural tissue, it is currently largely unknown whether similar effects can be shown at the neural population level using neurophysiological readouts of human cortex. Here we hypothesized that acute tRNS will increase the responsiveness of primary motor cortex (M1) when probed with transcranial magnetic stimulation. Neural responsiveness was operationalized via the well-known concept of the resting motor threshold (RMT). We showed that tRNS acutely decreases RMT. This effect was small, but it was consistently replicated across four experiments including d...

Gravity is a pervasive environmental stimulus and accurate graviception is required for optimal spatial orientation and postural stability. The primary graviceptors are the vestibular organs, which include angular velocity (semicircular canals) and linear acceleration (otolith organs) sensors. Graviception is degraded in patients with vestibular damage, resulting in spatial misperception and imbalance. Since minimal therapy is available for these patients, substantial effort has focused on developing a vestibular prosthesis or implant (VI) that reproduces information normally provided by the canals (since reproducing otolith function is very challenging technically). Prior studies demonstrated that angular eye velocity responses could be driven by canal-VI mediated angular head velocity information, but it remains unknown if a canal-VI could improve spatial perception and posture since these behaviors require accurate estimates of angular head position in space relative to gravity . Here, we tested the hyp...

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and their roles in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting response of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a...

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer’s disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI to assess MTL subregional activity in 21 young (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using 18F-Flortaucipir for tau and 11C-Pittsburgh compound B for amyloid-β. The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs. ...

The axon initial segment (AIS) is a specialized neuronal compartment in which synaptic input is converted into action potential output. This process is supported by a diverse complement of sodium, potassium, and calcium channels (CaV). Different classes of sodium and potassium channels are scaffolded at specific sites within the AIS, conferring unique functions, but how calcium channels are functionally distributed within the AIS is unclear. Here, we utilize conventional 2-photon laser scanning and diffraction-limited, high-speed spot 2-photon imaging to resolve action potential-evoked calcium dynamics in the AIS with high spatiotemporal resolution. In mouse layer 5 prefrontal pyramidal neurons, calcium influx was mediated by a mix of CaV2 and CaV3 channels that differentially localized to discrete regions. CaV3 functionally localized to produce nanodomain hotspots of calcium influx that coupled to ryanodine-sensitive stores, whereas CaV2 localized to non-hotspot regions. Thus, different pools of CaVs appe...