Responses Of Neurons Research Articles

Investigating the role of an immediate early gene FOS as a potential regulator of autophagic response to hypoglycemia in embryonic hypothalamic neurons.

Hypoglycemia-associated autonomic failure (HAAF) is a well-established complication of diabetes. Although HAAF has serious outcomes such as recurrent morbidity, coma, and death, the mechanisms of HAAF and its pathological components are largely unknown. Our previous studies have revealed that hypoglycemia is associated with the upregulation of an immediate early gene - FOS. In addition, it is documented that glucose deprivation activates neuronal autophagic activities. Therefore, the present study aimed to identify the role of FOS and one of the core components of the autophagy pathway, Beclin-1 (encoded by the BECN1 gene), in the regulation of autophagic mechanisms in embryonic hypothalamic neurons in response to hypoglycemic conditions. Embryonic Mouse Hypothalamic Cell Line N39 (mHypoE-N39 or N39) was cultured in reduced concentrations of glucose (2000, 900, 500, and 200 mg/L). Gene and protein expression, as well as immunofluorescence studies on autophagy were conducted under different reduced glucose concentrations in N39 hypothalamic neurons with and without FOS and BECN1 gene knockdowns (KD). The outcomes of the present study have demonstrated a significant increase in autophagosome formation and subsequent lysosomal degradation in the hypothalamic neurons in response to reduced glucose concentrations. This hypoglycemic response appears to be lowered to a similar extent in the FOS KD and BECN1 KD cells, albeit insignificantly from the negative control, is indicative of the involvement of FOS in the autophagic response of hypothalamic neurons to hypoglycemia. Moreover, the KD cells exhibited a change in morphology and reduced cell viability compared with the control cells. Our findings suggest that reduced FOS expression could potentially be associated with impaired autophagic activities that are dependent on BECN1, which could lead to decreased or blunted hypothalamic activation in response to hypoglycemia, and this, in turn, may contribute to the development of HAAF.

Profile analysis in the inferior colliculus: physiology and modeling studies

Profile-analysis is a strategy for assessing sensitivity to differences in spectral shape [Green, Oxford University Press, 1988]. Despite extensive behavioral data, the neuronal mechanisms underlying profile-analysis remain elusive. To bridge this gap, extracellular recordings were made in awake rabbit inferior colliculus (IC) and simulated using a computation model. The standard stimulus was a log-spaced, n-component, zero-phase, equal-amplitude complex tone, presented diotically. The central component was incremented in the target stimulus. The discharge rate as a function of characteristic frequency (CF) was inferred by shifting the stimulus spectrum past the CF of each neuron. When the increment frequency was near CF, IC neurons had rates that decreased as the increment increased, contradicting a simple energy-based code. In some cases, the differences between rates for target and standard were largest for stimuli with component spacing that yielded the lowest thresholds in listeners. Responses of IC neurons that were excited by amplitude-modulated stimuli were consistent with model predictions for profile-analysis stimuli [Maxwell et al., JASA 147, 3523 (2020), Guest et al., bioRxiv (2023)]; however, the models did not explain responses of other types of IC neurons. Potential factors contributing to this discrepancy, such as off-CF inhibition and chirp selectivity, will be further explored. Support: NIHR01-DC010813

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons.

Inhalant abuse is an important health issue especially among children and adolescents who often encounter these agents in the home. Research into the neurobiological targets of inhalants has lagged behind that of other drugs such as alcohol and psychostimulants. However, studies from our lab and others have begun to reveal how inhalants such as the organic solvent toluene affect neurons in key addiction related areas of the brain including the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. In the present study, we extend these findings and examine the effect of toluene on electrophysiological responses of pyramidal neurons in the basolateral amygdala BLA, a region important for generating emotional and reward based information needed to guide future behavior. Whole-cell patch-clamp electrophysiology recordings of BLA pyramidal neurons in rat brain slices were used to assess toluene effects on intrinsic excitability and excitatory glutamatergic synaptic transmission. Acute application of 3 mM but not 0.3 mM toluene produced a small but significant (~20%) increase in current-evoked action potential (AP) firing that reversed following washout of the toluene containing solution. The change in firing during exposure to 3 mM toluene was accompanied by selective changes in AP parameters including reduced latency to first spike, increased AP rise time and decay and a reduction in the fast after-hyperpolization. To examine whether toluene also affects excitatory synaptic signaling, we expressed channelrhodopsin-2 in medial prefrontal cortex neurons and elicited synaptic currents in BLA neurons via light pulses. Toluene (3 mM) reduced light-evoked AMPA-mediated synaptic currents while a lower concentration (0.3 mM) had no effect. The toluene-induced reduction in AMPA-mediated BLA synaptic currents was prevented by the cannabinoid receptor-1 antagonist AM281. These findings are the first to demonstrate effects of acute toluene on BLA pyramidal neurons and add to existing findings showing that abused inhalants such as toluene have significant effects on neurons in brain regions involved in natural and drug induced reward.

Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons

LAR-RPTPs are evolutionarily conserved presynaptic cell-adhesion molecules that orchestrate multifarious synaptic adhesion pathways. Extensive alternative splicing of LAR-RPTP mRNAs may produce innumerable LAR-RPTP isoforms that act as regulatory “codes” for determining the identity and strength of specific synapse signaling. However, no direct evidence for this hypothesis exists. Here, using targeted RNA sequencing, we detected LAR-RPTP mRNAs in diverse cell types across adult male mouse brain areas. We found pronounced cell-type–specific patterns of two microexons, meA and meB, in Ptprd mRNAs. Moreover, diverse neural circuits targeting the same neuronal populations were dictated by the expression of different Ptprd variants with distinct inclusion patterns of microexons. Furthermore, conditional ablation of Ptprd meA+ variants at presynaptic loci of distinct hippocampal circuits impaired distinct modes of synaptic transmission and object-location memory. Activity-triggered alterations of the presynaptic Ptprd meA code in subicular neurons mediates NMDA receptor-mediated postsynaptic responses in CA1 neurons and object-location memory. Our data provide the evidence of cell-type- and/or circuit-specific expression patterns in vivo and physiological functions of LAR-RPTP microexons that are dynamically regulated.

The anterior cingulate cortex controls the hyperactivity in subthalamic neurons in male mice with comorbid chronic pain and depression.

Neurons in the subthalamic nucleus (STN) become hyperactive following nerve injury and promote pain-related responses in mice. Considering that the anterior cingulate cortex (ACC) is involved in pain and emotion processing and projects to the STN, we hypothesize that ACC neurons may contribute to hyperactivity in STN neurons in chronic pain. In the present study, we showed that ACC neurons enhanced activity in response to noxious stimuli and to alterations in emotional states and became hyperactive in chronic pain state established by spared nerve injury of the sciatic nerve (SNI) in mice. In naïve mice, STN neurons were activated by noxious stimuli, but not by alterations in emotional states. Pain responses in STN neurons were attenuated in both naïve and SNI mice when ACC neurons were inhibited. Furthermore, optogenetic activation of the ACC-STN pathway induced bilateral hyperalgesia and depression-like behaviors in naive mice; conversely, inhibition of this pathway is sufficient to attenuate hyperalgesia and depression-like behaviors in SNI mice and naïve mice subjected to stimulation of STN neurons. Finally, mitigation of pain-like and depression-like behaviors in SNI mice by inhibition of the ACC-STN projection was eliminated by activation of STN neurons. Our results demonstrate that hyperactivity in the ACC-STN pathway may be an important pathophysiology in comorbid chronic pain and depression. Thus, the ACC-STN pathway may be an intervention target for the treatment of the comorbid chronic pain and depression.

Cholinergic Basal Forebrain Connectivity to the Basolateral Amygdala Modulates Food Intake.

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior.

Mechanical stimulation and electrophysiological monitoring at subcellular resolution reveals differential mechanosensation of neurons within networks

A growing consensus that the brain is a mechanosensitive organ is driving the need for tools that mechanically stimulate and simultaneously record the electrophysiological response of neurons within neuronal networks. Here we introduce a synchronized combination of atomic force microscopy, high-density microelectrode array and fluorescence microscopy to monitor neuronal networks and to mechanically characterize and stimulate individual neurons at piconewton force sensitivity and nanometre precision while monitoring their electrophysiological activity at subcellular spatial and millisecond temporal resolution. No correlation is found between mechanical stiffness and electrophysiological activity of neuronal compartments. Furthermore, spontaneously active neurons show exceptional functional resilience to static mechanical compression of their soma. However, application of fast transient (∼500 ms) mechanical stimuli to the neuronal soma can evoke action potentials, which depend on the anchoring of neuronal membrane and actin cytoskeleton. Neurons show higher responsivity, including bursts of action potentials, to slower transient mechanical stimuli (∼60 s). Moreover, transient and repetitive application of the same compression modulates the neuronal firing rate. Seemingly, neuronal networks can differentiate and respond to specific characteristics of mechanical stimulation. Ultimately, the developed multiparametric tool opens the door to explore manifold nanomechanobiological responses of neuronal systems and new ways of mechanical control.

Menthacarin treatment attenuates nociception in models of visceral hypersensitivity.

Chronic visceral hypersensitivity is closely associated with irritable bowel syndrome (IBS), a very common disorder which significantly impairs quality of life, characterized by abdominal pain, and distension. Imaging studies have found that IBS patients show higher metabolic activities and functional differences from normal controls in the anterior cingulate cortex (ACC), in response to visceral pain stimulation. Non-clinical data and clinical data suggest that medicinal products containing essential oils such as peppermint or caraway oil exert beneficial effects on IBS symptoms. We assessed acute and long-term treatment effects of a mixture of peppermint and caraway essential oils (Menthacarin) on brain electrophysiological markers of gut pain sensitivity in two rat models of visceral hypersensitivity. Chronic administration of corticosteroids and acute repeated mechanical hyperstimulation under anesthesia induced hyperalgesia and hypersensitivity, characterized by an increase in electrophysiological excitatory responses of ACC neurons to colorectal distension (CRD) and an increase in the proportion of neurons responding to otherwise subthreshold stimulation, respectively. Long-term, but not acute, oral administration of Menthacarin (60 mg kg-1 day-1) significantly reduced the net excitatory response to CRD in normally responsive control animals and counteracted the development of visceral hyperalgesia and hypersensitivity induced by repeated corticosterone administration and acute mechanical stimulation. The present study shows that, using the CRD method, chronic Menthacarin administration at a clinically relevant dose attenuates the neuronal discharge associated with visceral pain stimuli in the rat ACC, particularly in models of hypersensitivity, suggesting a potential for treating exaggerated visceral pain sensitivity.

Gene editing improves endoplasmic reticulum-mitochondrial contacts and unfolded protein response in Friedreich's ataxia iPSC-derived neurons.

Friedreich ataxia (FRDA) is a multisystemic, autosomal recessive disorder caused by homozygous GAA expansion mutation in the first intron of frataxin (FXN) gene. FXN is a mitochondrial protein critical for iron-sulfur cluster biosynthesis and deficiency impairs mitochondrial electron transport chain functions and iron homeostasis within the organelle. Currently, there is no effective treatment for FRDA. We have previously demonstrated that single infusion of wild-type hematopoietic stem and progenitor cells (HSPCs) resulted in prevention of neurologic and cardiac complications of FRDA in YG8R mice, and rescue was mediated by FXN transfer from tissue engrafted, HSPC-derived microglia/macrophages to diseased neurons/myocytes. For a future clinical translation, we developed an autologous stem cell transplantation approach using CRISPR/Cas9 for the excision of the GAA repeats in FRDA patients' CD34+ HSPCs; this strategy leading to increased FXN expression and improved mitochondrial functions. The aim of the current study is to validate the efficiency and safety of our gene editing approach in a disease-relevant model. We generated a cohort of FRDA patient-derived iPSCs and isogenic lines that were gene edited with our CRISPR/Cas9 approach. iPSC derived FRDA neurons displayed characteristic apoptotic and mitochondrial phenotype of the disease, such as non-homogenous microtubule staining in neurites, increased caspase-3 expression, mitochondrial superoxide levels, mitochondrial fragmentation, and partial degradation of the cristae compared to healthy controls. These defects were fully prevented in the gene edited neurons. RNASeq analysis of FRDA and gene edited neurons demonstrated striking improvement in gene clusters associated with endoplasmic reticulum (ER) stress in the isogenic lines. Gene edited neurons demonstrated improved ER-calcium release, normalization of ER stress response gene, XBP-1, and significantly increased ER-mitochondrial contacts that are critical for functional homeostasis of both organelles, as compared to FRDA neurons. Ultrastructural analysis for these contact sites displayed severe ER structural damage in FRDA neurons, that was undetected in gene edited neurons. Taken together, these results represent a novel finding for disease pathogenesis showing dramatic ER structural damage in FRDA, validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich's ataxia.

Calcium imaging of adult olfactory epithelium reveals amines as important odor class in fish.

The odor space of aquatic organisms is by necessity quite different from that of air-breathing animals. The recognized odor classes in teleost fish include amino acids, bile acids, reproductive hormones, nucleotides, and a limited number of polyamines. Conversely, a significant portion of the fish olfactory receptor repertoire is composed of trace amine-associated receptors, generally assumed to be responsible for detecting amines. Zebrafish possess over one hundred of these receptors, but the responses of olfactory sensory neurons to amines have not been known so far. Here we examined odor responses of zebrafish olfactory epithelial explants at the cellular level, employing calcium imaging. We report that amines elicit strong responses in olfactory sensory neurons, with a time course characteristically different from that of ATP-responsive (basal) cells. A quantitative analysis of the laminar height distribution shows amine-responsive cells undistinguishable from ciliated neurons positive for olfactory marker protein. This distribution is significantly different from those measured for microvillous neurons positive for transient receptor potential channel 2 and basal cells positive for proliferating cell nuclear antigen. Our results suggest amines as an important odor class for teleost fish.

Characterization and closed-loop control of infrared thalamocortical stimulation produces spatially constrained single-unit responses.

Deep brain stimulation (DBS) is a powerful tool for the treatment of circuitopathy-related neurological and psychiatric diseases and disorders such as Parkinson's disease and obsessive-compulsive disorder, as well as a critical research tool for perturbing neural circuits and exploring neuroprostheses. Electrically mediated DBS, however, is limited by the spread of stimulus currents into tissue unrelated to disease course and treatment, potentially causing undesirable patient side effects. In this work, we utilize infrared neural stimulation (INS), an optical neuromodulation technique that uses near to midinfrared light to drive graded excitatory and inhibitory responses in nerves and neurons, to facilitate an optical and spatially constrained DBS paradigm. INS has been shown to provide spatially constrained responses in cortical neurons and, unlike other optical techniques, does not require genetic modification of the neural target. We show that INS produces graded, biophysically relevant single-unit responses with robust information transfer in rat thalamocortical circuits. Importantly, we show that cortical spread of activation from thalamic INS produces more spatially constrained response profiles than conventional electrical stimulation. Owing to observed spatial precision of INS, we used deep reinforcement learning (RL) for closed-loop control of thalamocortical circuits, creating real-time representations of stimulus-response dynamics while driving cortical neurons to precise firing patterns. Our data suggest that INS can serve as a targeted and dynamic stimulation paradigm for both open and closed-loop DBS.

Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

Eph receptor tyrosine kinases participate in a variety of normal and pathogenic processes during development and throughout adulthood. This versatility is likely facilitated by the ability of Eph receptors to signal through diverse cellular signalling pathways: primarily by controlling cytoskeletal dynamics, but also by regulating cellular growth, proliferation, and survival. Despite many proteins linked to these signalling pathways interacting with Eph receptors, the specific mechanisms behind such links and their coordination remain to be elucidated. In a proteomics screen for novel EPHB2 multi-effector proteins, we identified human MYC binding protein 2 (MYCBP2 or PAM or Phr1). MYCBP2 is a large signalling hub involved in diverse processes such as neuronal connectivity, synaptic growth, cell division, neuronal survival, and protein ubiquitination. Our biochemical experiments demonstrate that the formation of a complex containing EPHB2 and MYCBP2 is facilitated by FBXO45, a protein known to select substrates for MYCBP2 ubiquitin ligase activity. Formation of the MYCBP2-EPHB2 complex does not require EPHB2 tyrosine kinase activity and is destabilised by binding of ephrin-B ligands, suggesting that the MYCBP2-EPHB2 association is a prelude to EPHB2 signalling. Paradoxically, the loss of MYCBP2 results in increased ubiquitination of EPHB2 and a decrease of its protein levels suggesting that MYCBP2 stabilises EPHB2. Commensurate with this effect, our cellular experiments reveal that MYCBP2 is essential for efficient EPHB2 signalling responses in cell lines and primary neurons. Finally, our genetic studies in Caenorhabditis elegans provide in vivo evidence that the ephrin receptor VAB-1 displays genetic interactions with known MYCBP2 binding proteins. Together, our results align with the similarity of neurodevelopmental phenotypes caused by MYCBP2 and EPHB2 loss of function, and couple EPHB2 to a signalling effector that controls diverse cellular functions.

Neuronal sensorimotor integration guiding salt concentration navigation in Caenorhabditis elegans

Animals navigate their environment by manipulating their movements and adjusting their trajectory which requires a sophisticated integration of sensory data with their current motor status. Here, we utilize the nematode Caenorhabditis elegans to explore the neural mechanisms of processing the sensory and motor information for navigation. We developed a microfluidic device which allows animals to freely move their heads while receiving temporal NaCl stimuli. We found that C. elegans regulates neck bending direction in response to temporal NaCl concentration changes in a way which is consistent with a C. elegans' navigational strategy which regulates traveling direction toward preferred NaCl concentrations. Our analysis also revealed that the activity of a neck motor neuron is significantly correlated with neck bending and activated by the decrease in NaCl concentration in a phase-dependent manner. By combining the analysis of behavioral and neural response to NaCl stimuli and optogenetic perturbation experiments, we revealed that NaCl decrease during ventral bending activates the neck motor neuron which counteracts ipsilateral bending. Simulations further suggest that this phase-dependent response of neck motor neurons can facilitate curving toward preferred salt concentrations.

Implications of variable synaptic weights for rate and temporal coding of cerebellar outputs.

Purkinje cell (PC) synapses onto cerebellar nuclei (CbN) neurons allow signals from the cerebellar cortex to influence the rest of the brain. PCs are inhibitory neurons that spontaneously fire at high rates, and many PC inputs are thought to converge onto each CbN neuron to suppress its firing. It has been proposed that PCs convey information using a rate code, a synchrony and timing code, or both. The influence of PCs on CbN neuron firing was primarily examined for the combined effects of many PC inputs with comparable strengths, and the influence of individual PC inputs has not been extensively studied. Here, we find that single PC to CbN synapses are highly variable in size, and using dynamic clamp and modeling we reveal that this has important implications for PC-CbN transmission. Individual PC inputs regulate both the rate and timing of CbN firing. Large PC inputs strongly influence CbN firing rates and transiently eliminate CbN firing for several milliseconds. Remarkably, the refractory period of PCs leads to a brief elevation of CbN firing prior to suppression. Thus, individual PC-CbN synapses are suited to concurrently convey rate codes and generate precisely timed responses in CbN neurons. Either synchronous firing or synchronous pauses of PCs promote CbN neuron firing on rapid time scales for nonuniform inputs, but less effectively than for uniform inputs. This is a secondary consequence of variable input sizes elevating the baseline firing rates of CbN neurons by increasing the variability of the inhibitory conductance. These findings may generalize to other brain regions with highly variable inhibitory synapse sizes.

Morphofunctional Characteristics of Dorsal Root Ganglion Neurons in the Dynamics of Healing of a Purulent Wound

Abstract. between the morphological and functional state of spinal ganglia neurons and the dynamics of healing of a purulent wound in an experimental animal during its natural course and complex therapy with hydropulse sanitation (HIS) and the addition of platelet-rich blood plasma (PRP). Material and methods. In an experiment on 100 white outbred rats, a purulent wound on the lateral surface of the thigh was modeled by introducing a daily culture of Staphyllococcus aureus. Two groups were formed: natural healing and healing after therapy with hydropulse sanitation of the wound with an isotonic NaCl solution followed by the addition of platelet-enriched autoplasma. The material for the study was taken on the 1st, 3rd, 5th, 7th, 14th, and 21st days. The area of the wound and the dynamics of its healing were assessed using the planimetric method. For the study, lumbar spinal ganglia (SG) of segments LIII–LV. were taken. At the light-optical level, after staining with cresyl violet according to Nissl and azure B according to the S. Shea method, the area of nerve cells was measured, photometry of RNA content was carried out, and the number of satellite gliocytes was counted. The obtained data were processed using statistical analysis methods. Results. The healing process of a purulent skin wound ended with the formation of a scar on days 7–14 for both experimental groups. The use of GIS and PRP demonstrated better dynamics of defect closure - a reduction in wound area by 59.35±3.4% (p=0.018) in the period from 3 to 5 days, compared with 40.05±2.9% (p=0.009) with natural healing. The response of SG neurons during healing was characterized by pronounced polymorphism. The maximum number of cells with reactive changes during natural healing was observed on the 5th day of the experiment (17.2±3.2% for A-neurons and 36.7±4.3% for B-neurons). Complex therapy led to a decrease in the proportion of both reactively altered and destructive neurons. The cell area, RNA content, and the number of satellite glia increased on average by the 7th day of the experiment. Separate close correlations were identified between the dynamics of changes in the wound area and the studied quantitative characteristics. Conclusion. A purulent wound causes a complex of nonspecific reactions in the neurons of the SG. In the dynamics of wound healing, neurons with reactive changes more often demonstrated biphasic dynamics, more pronounced for B-type cells with a primary reaction on days 1–3 and a further transition to regenerative hypertrophy or destruction. Regenerative changes in SG neurons had a close correlation with the processes of regeneration of the wound defect.

Negligible contribution of adaptation of ocular opponency neurons to the effect of short-term monocular deprivation.

Modeling work on binocular rivalry has described how ocular opponency neurons represent interocular conflict. These neurons have recently been considered to mediate an ocular dominance shift to the eye that has viewed a backward movie for long during which time the other eye is presented with a regular movie. Unlike typical short-term monocular deprivation, the visual inputs are comparable across eyes in that "dichoptic-backward-movie" paradigm. Therefore, it remains unclear whether the ocular opponency neurons are also responsible for the short-term monocular deprivation effect which is prevalently explained by the homeostatic compensation theory. We designed two experiments from distinct perspectives to investigate this question. In Experiment 1, we mitigated the imbalance in the activity of opponency neurons between the two eyes during monocular deprivation by presenting video stimuli alternately. In Experiment 2, we directly evaluated the response of opponency neurons before and after monocular deprivation using SSVEP techniques. Consistent with each other, both experiments failed to provide reliable evidence supporting the involvement of ocular opponency neurons in the short-term monocular deprivation effect. Our results suggest that ocular opponency neurons may not play an essential role in the short-term monocular deprivation effect, potentially due to interference from the homeostatic plasticity mechanism.

Neural stem cell homeostasis is affected in cortical organoids carrying a mutation in Angiogenin.

Mutations in Angiogenin (ANG) and TARDBP encoding the 43 kDa transactive response DNA binding protein (TDP-43) are associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). ANG is neuroprotective and plays a role in stem cell dynamics in the haematopoietic system. We obtained skin fibroblasts from members of an ALS-FTD family, one with mutation in ANG, one with mutation in both TARDBP and ANG, and one with neither mutation. We reprogrammed these fibroblasts to induced pluripotent stem cells (iPSCs) and generated cortical organoids as well as induced stage-wise differentiation of the iPSCs to neurons. Using these two approaches we investigated the effects of FTD-associated mutations in ANG and TARDBP on neural precursor cells, neural differentiation, and response to stress. We observed striking neurodevelopmental defects such as abnormal and persistent rosettes in the organoids accompanied by increased self-renewal of neural precursor cells. There was also a propensity for differentiation to later-born neurons. In addition, cortical neurons showed increased susceptibility to stress, which is exacerbated in neurons carrying mutations in both ANG and TARDBP. The cortical organoids and neurons generated from patient-derived iPSCs carrying ANG and TARDBP gene variants recapitulate dysfunctions characteristic of frontotemporal lobar degeneration observed in FTD patients. These dysfunctions were ameliorated upon treatment with wild type ANG. In addition to its well-established role during the stress response of mature neurons, ANG also appears to play a role in neural progenitor dynamics. This has implications for neurogenesis and may indicate that subtle developmental defects play a role in disease susceptibility or onset. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Role of Androgen Receptors in Mediation of Nandrolone Effects on Spatial Memory and Neuronal Response of Pyramidal Neurons in the Hippocampal CA1 Area

Background: Previously we have reported that intracerebroventricular microinjection of nandrolone decanoate (ND) improves spatial memory and hippocampal synaptic plasticity, but the underlying mechanism has not been clearly evaluated. The aim of this study was evaluated the role of androgen receptors (ARs) in the mediation of ND effects on spatial memory and neuronal response of pyramidal neurons of the hippocampal CA1 area. Materials and Methods: In the current study, the rats were divided into four groups: the control group received DMSO, while other experimental groups received ND (60 μg/2.5 μL), nilutamide (5 μg/2.5 μL), and co-administration of nilutamide (5 μg/2.5 μL) + ND (60 μg/2.5 μL) for 4 days. Spatial learning and memory were evaluated through the Morris water maze (MWM) test. Moreover, we test the electrophysiological properties of hippocampal plasticity by in vitro field potential recordings. In electrophysiological investigations, the field excitatory postsynaptic potentials (fEPSPs) and population spikes were recorded from the hippocampal slices taken from different groups. Results: At the behavioral level, our studies exhibited that escape latency and traveled distance in ND-treated rats significantly decreased during the MWM test’s training period, whereas administration of nilutamide before ND had no significant effect on escape latency and traveled distance in the MWM task. Furthermore, the results of field potential recording showed that the magnitude of fEPSP-long-term potentiation (LTP) of the ND-treated group was higher than the control group, while preadministration of nilutamide abolished the ND improvement effect on the magnitude of fEPSP-LTP. Conclusion: This study suggests that the administration of ND induces improvement in spatial memory and hippocampal synaptic plasticity through activation of central ARs.

Synchronization analysis of time series obtained from anesthetized rats during painful action

The purpose of this work is to determine the possibility of detecting changes in the relationships between such physiological rhythms as the activity of neurons in the reticular formation of the medulla oblongata, fluctuations in the blood pressure and respiration in anesthetized rats before and during the development of a pathological state associated with painful colorectal distension. This stretch mimics the pain localized in the lower abdomen in patients with irritable bowel syndrome and it is accompanied by responses of the brain neurons, fluctuations in the blood pressure and respiration. The analysis of changes in the relationships of these rhythms consisted in identifying phase synchronization between the time series of the variability of neuronal activity intervals and the variability of blood pressure intervals at the respiratory rate before and during pain exposure. Methods. To solve this problem, the synchrosqueezed wavelet transform method was applied, which makes it possible to effectively calculate the instantaneous frequencies and phases of non-stationary signals. As indicators of synchronization, we used the values of the index and the duration of phase synchronization as a time interval during which the value of the synchronization index is close to 1. Results. It has been established that the pain effect provides an adjustment of the frequency of the neuronal activity variability and the occurrence of synchronization between this activity and the blood pressure variability at the respiratory rate or causes an adjustment of the frequency of the blood pressure variability and the occurrence of synchronization between the blood pressure variability and the respiratory rhythm. It was found that the pain effect increases the duration of phase synchronization between the variability of the blood pressure and the respiratory rhythm or reduces the duration of phase synchronization between the variability of neuronal activity and the respiratory rhythm. Conclusion. The effect of painful colorectal distension on changes in the parameters of phase synchronization between physiological rhythms in anesthetized rats was studied in detail.

Adaptation of the inferior temporal neurons and efficient visual processing.

Numerous studies examining the responses of individual neurons in the inferior temporal (IT) cortex have revealed their characteristics such as two-dimensional or three-dimensional shape tuning, objects, or category selectivity. While these basic selectivities have been studied assuming that their response to stimuli is relatively stable, physiological experiments have revealed that the responsiveness of IT neurons also depends on visual experience. The activity changes of IT neurons occur over various time ranges; among these, repetition suppression (RS), in particular, is robustly observed in IT neurons without any behavioral or task constraints. I observed a similar phenomenon in the ventral visual neurons in macaque monkeys while they engaged in free viewing and actively fixated on one consistent object multiple times. This observation indicates that the phenomenon also occurs in natural situations during which the subject actively views stimuli without forced fixation, suggesting that this phenomenon is an everyday occurrence and widespread across regions of the visual system, making it a default process for visual neurons. Such short-term activity modulation may be a key to understanding the visual system; however, the circuit mechanism and the biological significance of RS remain unclear. Thus, in this review, I summarize the observed modulation types in IT neurons and the known properties of RS. Subsequently, I discuss adaptation in vision, including concepts such as efficient and predictive coding, as well as the relationship between adaptation and psychophysical aftereffects. Finally, I discuss some conceptual implications of this phenomenon as well as the circuit mechanisms and the models that may explain adaptation as a fundamental aspect of visual processing.