Stimulation Of Neurons Research Articles

Effects of dendritic Ca2+ spike on the modulation of spike timing with transcranial direct current stimulation in cortical pyramidal neurons.

Transcranial direct current stimulation (tDCS) generates a weak electric field (EF) within the brain, which induces opposite polarization in the soma and distal dendrite of cortical pyramidal neurons. The somatic polarization directly affects the spike timing, and dendritic polarization modulates the synaptically evoked dendritic activities. Ca2+ spike, the most dramatic dendritic activity, is crucial for synaptic integration and top-down signal transmission, thereby indirectly influencing the output spikes of pyramidal cells. Nevertheless, the role of dendritic Ca2+ spike in the modulation of neural spike timing with tDCS remains largely unclear. In this study, we use morphologically and biophysically realistic models of layer 5 pyramidal cells (L5 PCs) to simulate the dendritic Ca2+ spike and somatic Na+ spike in response to distal dendritic synaptic inputs under weak EF stimulation. Our results show that weak EFs modulate the spike timing through the modulation of dendritic Ca2+ spike and somatic polarization, and such field effects are dependent on synaptic inputs. At weak synaptic inputs, the spike timing is advanced due to the facilitation of dendritic Ca2+ spike by field-induced dendritic depolarization. Conversely, it is delayed by field-induceddendritic hyperpolarization. In this context, the Ca2+ spike exhibits heightened sensitivity to weak EFs, thereby governing the changes in spike timing. At strong synaptic inputs, somatic polarization dominates the changes in spike timing due to the decreased sensitivity of Ca2+ spike to EFs. Consequently, the spike timing is advanced/delayed by field-induced somatic depolarization/hyperpolarization. Moreover, EFs have significant effects on the changes in the timing of somatic spike and Ca2+ spike when synaptic current injection coincides with the onset of EFs. Field effects on spike timing follow a cosine dependency on the field polar angle, with maximum effects in the field direction parallel to the somato-dendritic axis. Furthermore, our results are robust to morphological and biological diversity. These findings clarify the modulation of spike timing with weak EFs and highlight the crucial role of dendritic Ca2+ spike. These predictions shed light on the neural basis of tDCS and should be considered when understanding the effect of tDCS on population dynamics and cognitive behavior.

Stimulation of Locus Ceruleus Inputs to the Prelimbic Cortex in Mice Induces Cell Type-Specific Expression of the Apoe Gene.

The medial frontal cortex (mFC) and locus ceruleus (LC) are two brain areas that have been implicated in a range of cognitive phenomena, such as attention, memory, and decision-making. Regulators of these brain regions at the molecular level are not well understood but might help to elucidate underlying mechanisms of disorders that present with deficits in these cognitive domains. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the prelimbic subregion (PrL) of the mFC and subsequent bulk RNA sequencing from the mouse PrL. We found that stimulation of this circuit caused an increase in transcription of a host of genes, including the Apoe gene. To investigate cell type-specific expression of Apoe in the PrL, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the PrL or a control virus and found that increases in Apoe expression in the PrL following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in a cortical microcircuit that is important for attention, memory, and decision-making and point to interneuron-specific expression of Apoe as a potential biomarker for circuit function in disorders such as attention-deficit hyperactivity disorder, schizophrenia, and Alzheimer's disease.

Activation of Centromedial Amygdala GABAergic Neurons Produces Hypotension in Mice.

The central amygdala (CeA) is a crucial modulator of emotional, behavioral, and autonomic functions, including cardiovascular responses. Despite its importance, the specific circuit by which the CeA modulates blood pressure remains insufficiently explored. Our investigations demonstrate that photostimulation of GABAergic neurons in the centromedial amygdala (CeMGABA), as opposed to those in the centrolateral amygdala (CeL), produces a depressor response in both anesthetized and freely-moving mice. In addition, activation of CeMGABA axonal terminals projecting to the nucleus tractus solitarius (NTS) significantly reduces blood pressure. These CeMGABA neurons form synaptic connections with NTS neurons, allowing for the modulation of cardiovascular responses by influencing the caudal or rostral ventrolateral medulla. Furthermore, CeMGABA neurons targeting the NTS receive dense inputs from the CeL. Consequently, stimulation of CeMGABA neurons elicits hypotension through the CeM-NTS circuit, offering deeper insights into the cardiovascular responses associated with emotions and behaviors.

Synapse-to-nucleus ERK-CREB transcriptional signaling requires dendrite-to-soma Ca2+propagation mediated by L-type voltage-gated Ca2+ channels.

The cAMP-response element binding protein (CREB) transcription factor controls the expression of the neuronal immediate early genes c-Fos, Arc, and Bdnf and is essential for long-lasting synaptic plasticity underlying learning and memory. Despite this critical role, there is still ongoing debate regarding the synaptic excitation-transcription (E-T) coupling mechanisms mediating CREB activation in the nucleus. Here we employed optical uncaging of glutamate to mimic synaptic excitation of distal dendrites in conjunction with simultaneous imaging of intracellular Ca2+ dynamics and transcriptional reporter gene expression to elucidate CREB E-T coupling mechanisms in hippocampal neurons cultured from both male and female rats. Using this approach, we found that CREB-dependent transcription was engaged following dendritic stimulation of N-methyl, D-aspartate receptors (NMDARs) only when Ca2+ signals propagated to the soma via subsequent activation of L-type voltage-gated Ca2+ channels resulting in activation of Extracellular signal-Regulated Kinase (ERK) MAP kinase signaling to sustain CREB phosphorylation in the nucleus. In contrast, dendrite-restricted Ca2+ signals generated by NMDARs failed to stimulate CREB-dependent transcription. Furthermore, Ca2+-CaM-dependent kinase (CaMK)-mediated signaling pathways that may transiently contribute to CREB-phosphorylation following stimulation were ultimately dispensable for downstream CREB-dependent transcription and c-Fos induction. These findings emphasize the essential role that L-type Ca2+ channels play in rapidly relaying signals over long distances from synapses located on distal dendrites to the nucleus to control gene expression.Significance Statement The transcription factor CREB controls gene expression programs required for long-lasting synaptic plasticity and learning and memory, yet the synapse-to-nucleus signaling mechanisms mediating CREB activation are still unclear. Using glutamate uncaging to mimic synaptic input to dendrites, this study shows that Ca2+ signals propagated to the soma by L-type voltage-gated Ca2+ channels engage the ERK MAP kinase cascade to mediate CREB phosphorylation and CREB-dependent transcription. In contrast, dendrite-restricted Ca2+ signals generated primarily by NMDARs failed to effectively engage this signaling pathway or CREB-dependent transcription. In addition, we found that while ERK and CaMK pathways may both contribute to increased CREB phosphorylation immediately following neuronal stimulation, sustained ERK signaling to CREB was necessary to effectively drive CREB-dependent transcription.

Solid-State Nanopores for Spatially Resolved Chemical Neuromodulation.

Most neural prosthetic devices are based on electrical stimulation, although the modulation of neuronal activity by a localized chemical delivery would better mimic physiological synaptic machinery. In the past decade, various drug delivery approaches attempted to emulate synaptic transmission, although they were hampered by poor retention of their cargo while reaching the target destination, low spatial resolution, and poor biocompatibility and stability of the materials involved. Here, we propose a planar solid-state device for multisite neurotransmitter translocation at the nanoscale consisting of a nanopatterned ceramic membrane connected to a reservoir designed to store neurotransmitters. We achieved diffusion-mediated glutamate stimulation of primary neurons, while we showed the feasibility to translocate other molecules through the pores by either pressure or diffusion, proving the versatility of the proposed technology. Finally, the system proved to be a promising neuronal stimulation interface in mice and nonhuman primates ex vivo, paving the way toward a biomimetic chemical stimulation in neural prosthetics and brain machine interfaces.

Piezoelectric Nanoparticle-Based Ultrasound Wireless Piezoelectric Neuromodulation Inhibits Epileptiform Activity of Primary Neurons.

Piezoelectric materials, renowned for their ability to convert mechanical energy into electrical energy, have gained attention for their potential in biomedical applications. In particular, piezoelectric nanoparticles, such as barium titanate nanoparticles, hold great promise for treating neurologically related diseases. In this study, barium titanate piezoelectric nanoparticles are used as stimulators to directly treat epileptic neurons. After being modified by polyethylene glycol, barium titanate nanoparticles have shown excellent biocompatibility and dispersibility. Furthermore, such nanoparticles offer wireless piezoelectric stimulation to neurons in response to low-intensity pulsed ultrasound. More importantly, our experiments reveal that piezoelectric stimulation immediately reduces neuronal intracellular calcium concentration and restores cell viability. These effects are attributed to the opening of voltage-gated calcium channels and the release of active substances. These findings offer insights into the potential of piezoelectric stimulation as an approach for epilepsy treatment and enhance our understanding of the mechanisms underlying electrical stimulation in epileptic neurons.

CNSC-28. BRAINSTEM NEUROMODULATORY NEURONS PROMOTE GLIOMA GROWTH LOCALLY AND VIA LONG-RANGE PROJECTIONS TO MIDLINE AND CORTICAL STRUCTURES

Abstract Neuronal activity robustly drives glioma progression, mediated through paracrine and synaptic neuron-to-glioma interactions. Recent research has focused on glutamatergic and GABAergic neurons, while the impact of neuromodulatory neuron subpopulations and their long-range projections remain unexplored. Here, we explore the glioma-promoting effects of serotonergic and cholinergic brainstem neurons, which project to defined regions throughout the brain. By employing optogenetic stimulation of midbrain serotonergic or cholinergic neurons in mice bearing high-grade glioma allografts or xenografts, we observed robust, circuit-specific effects of each neuromodulatory neuronal subtype on proliferation. Concordant with the anatomy of serotonergic projections, we found that serotonergic neurons of the dorsal raphe nucleus promoted glioma proliferation in the neocortex and pons, while those from the median raphe nucleus increased proliferation in the thalamus. Similarly, stimulation of cholinergic neurons in the laterodorsal tegmentum nucleus enhanced thalamic glioma growth, and stimulation of the pedunculopontine nucleus promoted pontine tumor growth. The long-range neuronal activity-regulated effects on glioma cells were mediated by neurotransmitter secretion at axon terminals, and paracrine signalling protein release locally in the brainstem. The activity-regulated paracrine factor profiles are distinct between serotonergic and cholinergic neurons, illustrating neuron subtype-specific mechanisms affecting glioma cells beyond neurotransmitter differences. Co-culture with hESC/hiPSC-derived cholinergic or serotonergic neurons demonstrated synaptic structures between both neuromodulatory subpopulations and glioma cells, indicating a synaptic component to these neuron-glioma interactions. ScRNA-seq data integration revealed distinct receptor abundances between DMGs and IDH-WT glioblastomas correlating with specific cellular states. Inhibition of these targets – such as M1 or M3 cholinergic receptors in DMG – mitigated the proliferation-inducing effects of the relevant neuron subtype on glioma cells. In summary, these findings introduce brainstem cholinergic and serotonergic neuromodulatory neurons as drivers of high-grade glioma growth in a circuit-specific manner in midline structures and in neocortex, adding to the complexity with which gliomas integrate into brain-wide neural circuitry.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

Hypothalamic corticotropin-releasing hormone neurons modulate sevoflurane anesthesia and the post-anesthesia stress responses.

General anesthesia (GA) is an indispensable procedure necessary for safely and compassionately administering a significant number of surgical procedures and invasive diagnostic tests. However, the undesired stress response associated with GA causes delayed recovery and even increased morbidity in the clinic. Here, a core hypothalamic ensemble, corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (PVHCRH neurons), is discovered to play a role in regulating sevoflurane GA. Chemogenetic activation of these neurons delay the induction of and accelerated emergence from sevoflurane GA, whereas chemogenetic inhibition of PVHCRH neurons accelerates induction and delays awakening. Moreover, optogenetic stimulation of PVHCRH neurons induce rapid cortical activation during both the steady and deep sevoflurane GA state with burst-suppression oscillations. Interestingly, chemogenetic inhibition of PVHCRH neurons relieve the sevoflurane GA-elicited stress response (e.g., excessive self-grooming and elevated corticosterone level). These findings identify PVHCRH neurons modulate states of anesthesia in sevoflurane GA, being a part of anesthesia regulatory network of sevoflurane.

A normative framework dissociates need and motivation in hypothalamic neurons.

Physiological needs evoke motivational drives that produce natural behaviors for survival. In previous studies, the temporally intertwined dynamics of need and motivation have made it challenging to differentiate these two components. On the basis of classic homeostatic theories, we established a normative framework to derive computational models for need-encoding and motivation-encoding neurons. By combining the model-based predictions and naturalistic experimental paradigms, we demonstrated that agouti-related peptide (AgRP) and lateral hypothalamic leptin receptor (LHLepR) neuronal activities encode need and motivation, respectively. Our model further explains the difference in the dynamics of appetitive behaviors induced by optogenetic stimulation of AgRP or LHLepR neurons. Our study provides a normative modeling framework that explains how hypothalamic neurons separately encode need and motivation in the mammalian brain.

An infralimbic cortex neuronal ensemble encoded during learning attenuates fear generalization expression.

Generalization allows previous experience to adaptively guide behavior when conditions change. The infralimbic (IL) subregion of the ventral medial prefrontal cortex plays a known role in generalization processes, although mechanisms remain unclear. A basic physical unit of memory storage and expression in the brain are sparse, distributed groups of neurons known as ensembles (i.e., the engram). Here, we set out to determine whether neuronal ensembles established in the IL during learning contribute to generalized responses. Generalization was tested in male and female mice by presenting a novel, ambiguous, tone generalization stimulus following Pavlovian defensive (fear) conditioning. The first experiment was designed to test a role for IL in generalization using chemogenetic manipulations. Results show IL regulates defensive behavior in response to ambiguous stimuli. IL silencing led to a switch in defensive state, from vigilant scanning to generalized freezing, while IL stimulation reduced freezing in favor of scanning. Leveraging activity-dependent "tagging" technology (ArcCreER T2 x eYFP system), a neuronal ensemble, preferentially located in IL Layer 2/3, was associated with the generalization stimulus. Remarkably, in the identical discrete location, fewer reactivated neurons were associated with the generalization stimulus at the remote timepoint (30 days) following learning. When an IL neuronal ensemble established during learning was selectively chemogenetically silenced, generalization increased. Conversely, IL neuronal ensemble stimulation reduced generalization. Overall, these data identify a crucial role for IL in suppressing generalized responses. Further, an IL neuronal ensemble, formed during learning, functions to later attenuate the expression of generalization in the presence of ambiguous threat stimuli.

Bilateral chemogenetic activation of intratelencephalic neurons in motor cortex reduces spontaneous locomotor activity in mice

Intra-telencephalic neurons are a crucial class of cortical principal neurons that heavily innervate the striatum and cortical areas bilaterally. Their extensive cortico-cortical and cortico-striatal connectivity enables sensorimotor integration within the telencephalon, but their role in motor control remains poorly understood. Here, we used a chemogenetic approach to explore the role of intra-telencephalic neurons in spontaneous locomotor activity. Bilateral chemogenetic activation of intra-telencephalic Tlx3+ neurons in the mouse motor cortex reduced spontaneous locomotor activity in the open field, increasing states of freezing and immobility. This anti-motor effect was achieved in separate experiments with either administration of two chemogenetic actuators, clozapine N-oxide and deschloroclozapine. A systemic administration of the dopamine D1 receptor agonist SKF82958 reversed the chemogenetic effect on locomotor activity. Selective chemogenetic stimulation of intra-telencephalic neurons was confirmed through post-mortem c-Fos quantification in cortical layer 5 Tlx3+ neurons. The results establish a causal link between the activity level of intra-telencephalic neurons in the motor cortex, spontaneous locomotor activity in the open field, and the dopamine system. The findings are compatible with the hypothesis that intra-telencephalic neurons regulate spontaneous motor behavior via its bilateral cortico-striatal projections.

Optogenetic activation of mesencephalic projections to the nucleus accumbens shell impairs probabilistic reversal learning by disrupting learning from negative reinforcement.

Cognitive flexibility, the capacity to adapt behaviour to changes in the environment, is impaired in a range of brain disorders, including schizophrenia and Parkinson's disease. Putative neural substrates of cognitive flexibility include mesencephalic pathways to the ventral striatum (VS) and dorsomedial striatum (DMS), hypothesized to encode learning signals needed to maximize rewarded outcomes during decision-making. However, it is unclear whether mesencephalic projections to the ventral and dorsal striatum are distinct in their contribution to flexible reward-related learning. Here, rats acquired a two-choice spatial probabilistic reversal learning (PRL) task, reinforced on an 80%|20% basis (correct|incorrect responses) that assessed the flexibility of behaviour to repeated reversals of response-outcome contingencies. We report that optogenetic stimulation of projections from the ventral tegmental area (VTA) to the nucleus accumbens shell (NAcS) in the VS significantly impaired reversal learning when optical stimulation was temporally aligned with negative feedback (i.e., reward omission). VTA → NAcS stimulation during other phases of the behavioural task was without significant effect. Optogenetic stimulation of projection neurons from the substantia nigra (SN) to the DMS, aligned either with reward receipt or omission or prior to making a choice, had no significant effect on reversal learning. These findings are consistent with the notion that increased activity in the VTA → NAcS pathway disrupts behavioural flexibility by impairing learning from negative reinforcement.

Posterior Basolateral Amygdala is a Critical Amygdaloid Area for Temporal Lobe Epilepsy.

The amygdaloid complex consists of multiple nuclei and is a key node in controlling temporal lobe epilepsy (TLE) in both human and animal model studies. However, the specific nucleus in the amygdaloid complex and the neural circuitry governing seizures remain unknown. Here, it is discovered that activation of glutamatergic neurons in the posterior basolateral amygdala (pBLA) induces severe seizures and even mortality. The pBLA glutamatergic neurons project collateral connections to multiple brain regions, including the insular cortex (IC), bed nucleus of the stria terminalis (BNST), and central amygdala (CeA). Stimulation of pBLA-targeted IC neurons triggers seizures, whereas ablation of IC neurons suppresses seizures induced by activating pBLA glutamatergic neurons. GABAergic neurons in the BNST and CeA establish feedback inhibition on pBLA glutamatergic neurons. Deleting GABAergic neurons in the BNST or CeA leads to sporadic seizures, highlighting their role in balancing pBLA activity. Furthermore, pBLA neurons receive glutamatergic inputs from the ventral hippocampal CA1 (vCA1). Ablation of pBLA glutamatergic neurons mitigates both acute and chronic seizures in the intrahippocampal kainic acid-induced mouse model of TLE. Together, these findings identify the pBLA as a pivotal nucleus in the amygdaloid complex for regulating epileptic seizures in TLE.

Application of Optogenetics in the Regulation of Neural Circuits in Parkinson’s Disease

This paper reviews the application of optogenetics in the study of Parkinson’s disease and discuss how optogenetics stimulates specific neural circuits to regulate the symptoms and behaviors of Parkinson’s disease. Optogenetics technology has a higher spatial resolution than traditional electrical stimulation, and optogenetics can accurately control specific neuron populations, providing a new perspective for studying PD and exploring potential treatments. The researchers found that selective optogenetic stimulation of the dorsal striatum was sufficient to induce levodopalike dyskinesia in 6-hydroxydopamine (6-OHDA)-induced PD rat models. In addition, the researchers found that transplanted dopamine neurons can correct some of the motor deficits through their neural activity, including dopamine release and synaptic transmission. Although the utility of optogenetic techniques in human patients is unclear, the precise control of neural circuits in animal models provides an important way to understand the mechanisms and side effects of DBS therapy. The study also suggests that optogenetic stimulation of glutamatergic neurons in the mesocerebellar nucleus may improve motor function in PD mouse models, providing a new potential target for PD treatment. Finally, the article discusses how optogenetic technology can be transformed from a research tool into a treatment for PD, and how to repair damaged neural circuits through optogenetic technology to provide a more durable and effective treatment.

Cerebellar Purkinje cell activity regulates white matter response and locomotor function after neonatal hypoxia.

Neonatal hypoxia (Hx) causes white matter (WM) injury, particularly in the cerebellum. We previously demonstrated Hx-induced reduction of cerebellar Purkinje cell (PC) activity results in locomotor deficits. Yet, the mechanism of Hx-induced cerebellar WM injury and associated locomotor abnormalities remains undetermined. Here, we show that the cerebellar WM injury and linked locomotor deficits are driven by PC activity and are reversed when PC activity is restored. Using optogenetics and multielectrode array recordings, we manipulated PC activity and captured the resulting cellular responses in WM oligodendrocyte precursor cells and GABAergic interneurons. To emulate the effects of Hx, we used light activated Halorhodopsin targeted specifically to the PC layer of normal mice. Suppression of PC firing activity at P13 and P21 phenocopied the locomotor deficits observed in Hx. Moreover, histopathologic analysis of the developing cerebellar WM following PC inhibition (P21) revealed a corresponding reduction in oligodendrocyte maturation and myelination, akin to our findings in Hx mice. Conversely, PC stimulation restored PC activity, promoted oligodendrocyte maturation and enhanced myelination, resulting in reversed Hx-induced locomotor deficits. Our findings highlight the crucial role of PC activity in cerebellar WM development and locomotor performance following neonatal injury.Significance statement Adult survivors of prematurity often experience locomotor incoordination secondary to cerebellar dysfunction. The cerebellum develops in the last trimester of pregnancy, a period that preterm neonates miss. Here, we show how neonatal hypoxia alters the crosstalk between neurons and oligodendrocytes in the developing cerebellum. Through loss-of-function and gain-of-function experiments, we unveiled that neuronal activity drives cerebellum-associated white matter injury and locomotor dysfunction after hypoxia. Importantly, restoring neuronal activity using direct neurophysiological stimulation reversed the hypoxia-induced white matter injury and locomotor deficits. Early cerebellar neuronal stimulation could serve as a potential therapeutic intervention for locomotor dysfunction in neonates.

Aldosterone-induced salt appetite requires HSD2 neurons.

Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption may worsen end-organ damage in patients with aldosteronism. Preventing this increase could improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we previously identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). In the present study, we identified HSD2 neurons in the human brain, then used a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirmed that dietary sodium deprivation increases aldosterone production, salt intake, and HSD2 neuron activity. Next, we showed that continuous chemogenetic stimulation of HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that these neurons are necessary for aldosterone-induced salt intake. Identifying HSD2 neurons in the human brain and establishing their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.

Effectiveness of CI as an alternative to ABI for hearing loss in patients with vestibular schwannomas: A multicenter study in Japan

ObjectiveNF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS), often causing severe damage to the bilateral auditory function. Auditory brainstem implantation (ABI) provides hearing-impaired patients with an opportunity to reacquire auditory sensation through electrical stimulation of auditory neurons in the cochlear nucleus. However, ABI is not covered by public health insurance in Japan, leading to a large difference in financial burden compared to cochlear implantation (CI). The aim of the present study was to demonstrate the effectiveness of CI as an alternative to ABI for hearing reacquisition in patients with profound hearing loss caused by VS. MethodsTo investigate the current situation of ABI and CI for hearing reconstruction in VS patients, we conducted a questionnaire survey of 102 facilities in Japan. Based on the responses to the questionnaire, a multicenter research group consisting of otolaryngologists and neurosurgeons was established. We collected detailed data on patients with VS who underwent ABI (n = 7, all NF2) and CI (n = 14 [nine NF2, and five non-NF2]). ResultsSome sense of hearing was obtained in all patients but one with CI indicating the efficacy of CI and ABI for profound hearing loss caused by VS. The mean hearing levels were 45.4 dB HL in the ABI patients and 32.7 dB HL in the CI patients, indicating that CI was effective as an alternative to ABI. ConclusionThe results of the present study suggest the effectiveness of CI as an alternative to ABI for hearing reacquisition in patients with profound hearing loss caused by VS. Level of evidence4.

Vortex Nanodiscs Functionalization to Overcome Macrophage Recognition for Efficient Theragnosis Applications

Biological barriers prevent nanotherapeutics successful accumulation at target cells, limiting diagnosis and treatment responses. Magnetic nanodiscs with a spin‐vortex ground state have shown great promise for magnetomechanical cancer cells annihilation and for neuronal stimulation, requiring very low concentrations for an effective result. However, the biological barriers that these particles encounter upon intravenous administration remain a challenge. Herein, the synthesis of biocompatible multilayered Au/Fe/Au nanodiscs with a spin‐vortex ground state and their inert surface modification is reported. Two different surface modifications with two distinct polyethylene glycol (PEG) molecules are performed, which successfully reduce macrophage uptake, while maintaining the nanodiscs’ biocompatibility. By effectively preventing nanodisc uptake, innovative design features can be rationally incorporated to create a new generation of specific nanotherapeutics by modifying the PEG surface with specific targeting molecules.

A hypothalamic circuit mechanism underlying the impact of stress on memory and sleep.

Stress profoundly affects sleep and memory processes. Stress impairs memory consolidation, and similarly, disruptions in sleep compromise memory functions. Yet, the neural circuits underlying stress-induced sleep and memory disturbances are still not fully understood. Here, we show that activation of CRHPVN neurons, similar to acute restraint stress, decreases sleep and impairs memory in a spatial object recognition task. Conversely, inhibiting CRHPVN neurons during stress reverses stress-induced memory deficits while slightly increasing the amount of sleep. We found that both stress and stimulation of CRHPVN neurons activate neurons in the lateral hypothalamus (LH), and that their projections to the LH are critical for mediating stress-induced memory deficits and sleep disruptions. Our results suggest a pivotal role for CRHPVN neuronal pathways in regulating the adverse effects of stress on memory and sleep, an important step towards improving sleep and ameliorating the cognitive deficits that occur in stress-related disorders.