Cortical interneurons can be categorized into distinct populations based on multiple modalities, including molecular signatures and morpho-electrical (M/E) properties. Recently, many transcriptomic signatures based on single-cell RNA-seq have been identified in cortical interneurons. However, whether different interneuron populations defined by transcriptomic signature expressions correspond to distinct M/E subtypes is still unknown. Here, we applied the Patch-PCR approach to simultaneously obtain the M/E properties and messenger RNA (mRNA) expression of >600 interneurons in layer V of the mouse somatosensory cortex (S1). Subsequently, we identified 11 M/E subtypes, 9 neurochemical cell populations (NCs), and 20 transcriptomic cell populations (TCs) in this cortical lamina. Further analysis revealed that cells in many NCs and TCs comprised several M/E types and were difficult to clearly distinguish morpho-electrically. A similar analysis of layer V interneurons of mouse primary visual cortex (V1) and motor cortex (M1) gave results largely comparable to S1. Comparison between S1, V1, and M1 suggested that, compared to V1, S1 interneurons were morpho-electrically more similar to M1. Our study reveals the presence of substantial M/E variations in cortical interneuron populations defined by molecular expression.
Mice ; Animals ; Neocortex/physiology* ; Mice, Transgenic ; Interneurons/physiology*

Humans ; Astrocytes ; Neocortex ; Epilepsy/therapy* ; Tosylarginine Methyl Ester

Rheb (Ras homolog enriched in the brain) is a small GTPase protein that plays an important role in cell signaling for development of the neocortex through modulation of mTORC1 (mammalian-target-of-rapamycin-complex-1) activity. mTORC1 is known to control various biological processes including axonal growth in forming complexes at the lysosomal membrane compartment. As such, anchoring of Rheb on the lysosomal membrane via the farnesylation of Rheb at its cysteine residue (C180) is required for its promotion of mTOR activity. To test the significance of Rheb farnesylation, we overexpressed a farnesylation mutant form of Rheb, Rheb C180S, in primary rat hippocampal neurons and also in mouse embryonic neurons using in utero electroporation. Interestingly, we found that Rheb C180S maintained promotional effect of axonal elongation similar to the wild-type Rheb in both test systems. On the other hand, Rheb C180S failed to exhibit the multiple axon-promoting effect which is found in wild-type Rheb. The levels of phospho-4EBP1, a downstream target of mTORC1, were surprisingly increased in Rheb C180S transfected neurons, despite the levels of phosphorylated mTOR being significantly decreased compared to control vector transfectants. A specific mTORC1 inhibitor, rapamycin, also could not completely abolish axon elongation characteristics of Rheb C180S in transfected cells. Our data suggests that Rheb in a non-membrane compartment can promote the axonal elongation via phosphorylation of 4EBP1 and through an mTORC1-independent pathway.
Animals ; Axons ; Biological Processes ; Cysteine ; Electroporation ; GTP Phosphohydrolases ; Hand ; Membranes ; Mice ; Neocortex ; Neurons ; Phosphorylation ; Prenylation ; Protein Prenylation ; Rats ; Sirolimus ; TOR Serine-Threonine Kinases

The investigation of the embryonic development of the cerebellum has a long history. The postnatal normal development of the cerebellum in rodents and other animals became a popular topic for morphological investigations nearly a century ago. However, surprisingly, only a few studies are available regarding the prenatal normal development of the rodent cerebellum, especially in guinea pigs. Cell proliferation is essential for the development of the nervous system. The assessment of cell proliferation can be achieved by using various methods. In this study, we investigated the cell proliferation of the cerebellar cortex in guinea pigs at different stages of pregnancy and in postnatal life. Fetuses were obtained by cesarean section at 50 or 60 days of gestation (dg). Immunohistochemistry was performed with proliferating cell nuclear antigen (PCNA) antibody in the cerebellum. Strong PCNA immunoreactivity was observed in the external granular layer (EGL), which is a neurogenic zone in the cerebellum. The proportion of PCNA-IR cells was greater at 1 week than at 60 dg in lobule I, but not lobule VIII. After 50 dg, the width of the EGL continued to decline until 1 week, due to the maturation of the EGL cells. These results demonstrate the pattern of PCNA immunoreactivity in the developing cerebellum of guinea pigs. This serves as a guideline to study abnormal cerebellum development.
Animals ; Cell Proliferation ; Cerebellar Cortex ; Cerebellum ; Cesarean Section ; Embryonic Development ; Female ; Fetus ; Guinea Pigs ; Guinea ; Immunohistochemistry ; Neocortex ; Nervous System ; Pregnancy ; Proliferating Cell Nuclear Antigen ; Rodentia

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.
Action Potentials ; physiology ; Biomarkers ; metabolism ; Cell Culture Techniques ; Embryoid Bodies ; cytology ; metabolism ; Gene Expression ; Humans ; Induced Pluripotent Stem Cells ; cytology ; metabolism ; Lateral Ventricles ; cytology ; growth & development ; metabolism ; Microcephaly ; genetics ; metabolism ; pathology ; Models, Biological ; Mutation ; Neocortex ; cytology ; growth & development ; metabolism ; Nerve Tissue Proteins ; deficiency ; genetics ; Neurogenesis ; genetics ; Neurons ; cytology ; metabolism ; Organoids ; cytology ; metabolism ; PAX6 Transcription Factor ; genetics ; metabolism ; Patch-Clamp Techniques ; SOXB1 Transcription Factors ; genetics ; metabolism ; Zonula Occludens-1 Protein ; genetics ; metabolism

It has been reported that cross-frequency interactions may play an important role in local processing within thalamus and neocortex, as well as information transfer between subcortical and cortico-cortical brain regions. Strong commonalities in rhythmic network properties have been observed across recording techniques and task demands, but strong neuroscientific theories to situate such observations within a unified framework with direct relevance to explain neuropathologies remain scarce. Based on a comprehensive review of animal and human literature, we probe and introduce a neurophysiological framework to explain how coordinated cross-frequency and interregional oscillatory cortical dynamics underlie typical and atypical brain activation, and the formation of distributed functional ensembles supporting cortical networks underpinning perception and cognition. We propose that local regional activation by an external stimulus via a sensory pathway entails (1) attenuated alpha (8–14 Hz) and increased theta (4–8 Hz) and gamma (30–50 Hz) oscillatory activity, and (2) increased interactions among theta and gamma rhythms. These local dynamics also mediate the integration of activated neural populations into largescale functional assemblies through neuronal synchronization. This comprehensive perspective into the animal and human literature indicates a further thinking beyond synchrony and connectivity and the readiness for more hypothesis-driven research and modeling toward unified principles of thalamo-cortical processing. We further introduced such a possible framework: “The ATG switch”. We also discussed evidence that alpha-theta-gamma dynamics emerging from thalamocortical interactions may be implicated and disrupted in numerous neurological and neuropsychiatric conditions.
Animals ; Brain ; Cognition ; Gamma Rhythm ; Humans ; Neocortex ; Neurons ; Neuropathology ; Thalamus ; Thinking

The temporal lobe is essential in saving declarative memory and plays an important role along with the cerebral neocortex in creating and maintaining long-term memory. Damage to the temporal lobe is expected to result in cognitive impairment or dementia, which has characteristic symptoms such as cognitive and behavioral dysfunction and decreasing self-reliance in activities of daily living. We report on a patient, who suffered from dementia due to meningovascular syphilis affecting the medial temporal lobe, and on the outcome of cognitive rehabilitation.
Activities of Daily Living ; Dementia ; Humans ; Memory ; Memory, Long-Term ; Neocortex ; Syphilis ; Temporal Lobe

The temporal lobe is essential in saving declarative memory and plays an important role along with the cerebral neocortex in creating and maintaining long-term memory. Damage to the temporal lobe is expected to result in cognitive impairment or dementia, which has characteristic symptoms such as cognitive and behavioral dysfunction and decreasing self-reliance in activities of daily living. We report on a patient, who suffered from dementia due to meningovascular syphilis affecting the medial temporal lobe, and on the outcome of cognitive rehabilitation.
Activities of Daily Living ; Dementia ; Humans ; Memory ; Memory, Long-Term ; Neocortex ; Syphilis ; Temporal Lobe

BACKGROUND AND PURPOSE: There is growing interest in high-frequency oscillations (HFO) as electrophysiological biomarkers of the epileptic brain. We evaluated the clinical utility of interictal HFO events, especially their occurrence rates, by comparing the spatial distribution with a clinically determined epileptogenic zone by using subdural macroelectrodes. METHODS: We obtained intracranial electroencephalogram data with a high temporal resolution (2000 Hz sampling rate, 0.05-500 Hz band-pass filter) from seven patients with medically refractory epilepsy. Three epochs of 5-minute, artifact-free data were selected randomly from the interictal period. HFO candidates were first detected by an automated algorithm and subsequently screened to discard false detections. Validated events were further categorized as fast ripple (FR) and ripple (R) according to their spectral profiles. The occurrence rate of HFOs was calculated for each electrode contact. An HFO events distribution map (EDM) was constructed for each patient to allow visualization of the spatial distribution of their HFO events. RESULTS: The subdural macroelectrodes were capable of detecting both R and FR events from the epileptic neocortex. The occurrence rate of HFO events, both FR and R, was significantly higher in the seizure onset zone (SOZ) than in other brain regions. Patient-specific HFO EDMs can facilitate the identification of the location of HFO-generating tissue, and comparison with findings from ictal recordings can provide additional useful information regarding the epileptogenic zone. CONCLUSIONS: The distribution of interictal HFOs was reasonably consistent with the SOZ. The detection of HFO events and construction of spatial distribution maps appears to be useful for the presurgical mapping of the epileptogenic zone.
Biomarkers ; Brain ; Electrodes ; Electroencephalography ; Epilepsies, Partial ; Epilepsy ; Humans ; Neocortex ; Seizures

A new method of axon recording through axon bleb has boosted the studies on the functional role of central nervous system (CNS) axons. Using this method, we have revealed the mechanisms underlying the initiation and propagation of the digital-mode signal, all-or-none action potentials (APs), in neocortical pyramidal neurons. Accumulation of the low-threshold Na(+) channel subtype Na(v)1.6 at the distal end of the axon initial segment (AIS) determines the lowest threshold for AP initiation, whereas accumulation of the high-threshold subtype Na(v)1.2 at the proximal region of the AIS promotes AP backpropagation to the soma and dendrites. Through dual recording from the soma and the axon, we have showed that subthreshold membrane potential (V(m)) fluctuations in the soma propagate along the axon to a long distance and probably reach the axon terminals. Paired recording from cortical neurons has revealed that these V(m) changes in the soma modulate AP-triggered synaptic transmission. This new V(m)-dependent mode of synaptic transmission is called analog communication. Unique properties of axonal K(+) channels (K(v)1 channels) may contribute to shaping the AP waveform, particularly its duration, and thus controlling synaptic strength at different levels of presynaptic V(m). The level of background Ca(2+) may also participate in mediating the analog signaling. Together, these findings enrich our knowledge on the principles of neuronal signaling in the CNS and help understand how the brain works.
Action Potentials ; physiology ; Animals ; Axons ; physiology ; Central Nervous System ; cytology ; physiology ; Humans ; Membrane Potentials ; physiology ; NAV1.2 Voltage-Gated Sodium Channel ; physiology ; NAV1.6 Voltage-Gated Sodium Channel ; physiology ; Neocortex ; cytology ; physiology ; Patch-Clamp Techniques ; Pyramidal Cells ; physiology ; Sodium Channels ; physiology