Sukchan Lee

Tuning Thalamic Firing Modes via Simultaneous Modulation of T- and L-Type Ca2+ Channels Controls Pain Sensory Gating in the Thalamus

Two firing modes of thalamocortical (TC) neurons, tonic and burst firings, are thought to reflect the divergent states of sensory signal transmission from the thalamus to the cortex. However, the behavioral consequences of changes in the thalamic firing between the two modes have not been well demonstrated. Moreover, although the firing modes of TC neurons are known to be affected by corticothalamic inputs via thalamic metabotropic glutamate receptor type 1 (mGluR1)–phospholipase C β4 (PLCβ4) pathway, its molecular mechanisms have not been well elucidated. We addressed these questions using PLCβ4-deficient mice, which show decreased visceral pain responses. We demonstrate that burst and tonic firings of TC neurons are concomitantly regulated by PLCβ4 pathway. Blocking of this pathway by the mutation simultaneously increases bursting and decreases tonic firing of TC neurons through concurrent upregulation of T- and L-type Ca2+ currents. The mice with increased bursting and decreased tonic firing of TC neurons showed reduced visceral pain responses. Furthermore, we show that modulation of the Ca2+ channels or protein kinase C (PKC), a downstream molecule of PLCβ4, altered the firing modes of TC neurons and pain responses in the predicted ways. Our data demonstrate the molecular mechanism and behavioral consequences of altered firing modes of TC neurons in relaying the visceral pain signals. Our study also highlights the thalamic PLCβ4–PKC pathway as a “molecular switch” for the firing modes of TC neurons and thus for pain sensory gating.

Lateralization of observational fear learning at the cortical but not thalamic level in mice

Major cognitive and emotional faculties are dominantly lateralized in the human cerebral cortex. The mechanism of this lateralization has remained elusive owing to the inaccessibility of human brains to many experimental manipulations. In this study we demonstrate the hemispheric lateralization of observational fear learning in mice. Using unilateral inactivation as well as electrical stimulation of the anterior cingulate cortex (ACC), we show that observational fear learning is controlled by the right but not the left ACC. In contrast to the cortex, inactivation of either left or right thalamic nuclei, both of which are in reciprocal connection to ACC, induced similar impairment of this behavior. The data suggest that lateralization of negative emotions is an evolutionarily conserved trait and mainly involves cortical operations. Lateralization of the observational fear learning behavior in a rodent model will allow detailed analysis of cortical asymmetry in cognitive functions.

Bidirectional modulation of fear extinction by mediodorsal thalamic firing in mice

The mediodorsal thalamic nucleus has been implicated in the control of memory processes. However, the underlying neural mechanism remains unclear. Here we provide evidence for bidirectional modulation of fear extinction by the mediodorsal thalamic nucleus. Mice with a knockout or mediodorsal thalamic nucleus–specific knockdown of phospholipase C β4 exhibited impaired fear extinction. Mutant mediodorsal thalamic nucleus neurons in slices showed enhanced burst firing accompanied by increased T-type Ca2+ currents; blocking of T channels in vivo rescued the fear extinction. Tetrode recordings in freely moving mice revealed that, during extinction, the single-spike (tonic) frequency of mediodorsal thalamic nucleus neurons increased in wild-type mice, but was static in mutant mice. Furthermore, tonic-evoking microstimulations of the mediodorsal thalamic nucleus, contemporaneous with the extinction tones, rescued fear extinction in mutant mice and facilitated it in wild-type mice. In contrast, burst-evoking microstimulation suppressed extinction in wild-type mice, mimicking the mutation. These results suggest that the firing mode of the mediodorsal thalamic nucleus is critical for the modulation of fear extinction.

Translation of clock rhythmicity into neural firing in suprachiasmatic nucleus requires mGluR-PLCβ4 signaling

Phospholipase C β4 (PLCβ4) is expressed in the suprachiasmatic nucleus (SCN), as well as in tissues in the circadian entrainment pathway, including the retina and the lateral geniculate nucleus in the mouse. Using PLCβ4−/− mice, we previously reported that PLCβ4 is coupled to metabotropic glutamate receptors (mGluRs), which regulate the ionotropic glutamate responsiveness of SCN neurons, and thus were proposed to be involved in photic entrainment. We show here that the group-I mGluR–PLCβ4 signaling pathway is involved in translating circadian oscillations of the molecular clock into rhythmic outputs of SCN neurons.

Carbon-Nanotube-Modified Electrodes for Highly Efficient Acute Neural Recording

Microelectrodes are widely used for monitoring neural activities in various neurobiological studies. The size of the neural electrode is an important factor in determining the signal-to-noise ratio (SNR) of recorded neural signals and, thereby, the recording sensitivity. Here, it is demonstrated that commercial tungsten microelectrodes can be modified with carbon nanotubes (CNTs), resulting in a highly sensitive recording ability. The impedance with the respect to surface area of the CNT-modified electrodes (CNEs) is much less than that of tungsten microelectrodes because of their large electrochemical surface area (ESA). In addition, the noise level of neural signals recorded by CNEs is significantly less. Thus, the SNR is greater than that obtained using tungsten microelectrodes. Importantly, when applied in a mouse brain in vivo, the CNEs can detect action potentials five times more efficiently than tungsten microelectrodes. This technique provides a significant advance in the recording of neural signals, especially in brain regions with sparse neuronal densities.

Extrasynaptic GABAA Receptors in Mediodorsal Thalamic Nucleus Modulate Fear Extinction Learning

BackgroundThe gamma-amino-butyric acid (GABA) system is a critical mediator of fear extinction process. GABA can induce “phasic” or “tonic” inhibition in neurons through synaptic or extrasynaptic GABAA receptors, respectively. However, role of the thalamic “tonic GABA inhibition” in cognition has not been explored. We addressed this issue in extinction of conditioned fear in mice.ResultsHere, we show that GABAA receptors in the mediodorsal thalamic nucleus (MD) modulate fear extinction. Microinjection of gabazine, a GABAA receptor antagonist, into the MD decreased freezing behavior in response to the conditioned stimulus and thus facilitated fear extinction. Interestingly, microinjection of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a preferential agonist for the δ-subunit of extrasynaptic GABAA receptors, into the MD attenuated fear extinction. In the opposite direction, an MD-specific knock-out of the extrasynaptic GABAA receptors facilitated fear extinction.ConclusionsOur results suggest that “tonic GABA inhibition” mediated by extrasynaptic GABAA receptors in MD neurons, suppresses fear extinction learning. These results raise a possibility that pharmacological control of tonic mode of GABAA receptor activation may be a target for treatment of anxiety disorders like post-traumatic stress disorder.

The development of a PZT-based microdrive for neural signal recording

A hand-controlled microdrive has been used to obtain neural signals from rodents such as rats and mice. However, it places severe physical stress on the rodents during its manipulation, and this stress leads to alertness in the mice and low efficiency in obtaining neural signals from the mice. To overcome this issue, we developed a novel microdrive, which allows one to adjust the electrodes by a piezoelectric device (PZT) with high precision. Its mass is light enough to install on the mouse’s head. The proposed microdrive has three H-type PZT actuators and their guiding structure. The operation principle of the microdrive is based on the well known inchworm mechanism. When the three PZT actuators are synchronized, linear motion of the electrode is produced along the guiding structure. The electrodes used for the recording of the neural signals from neuron cells were fixed at one of the PZT actuators. Our proposed microdrive has an accuracy of about 400 nm and a long stroke of about 5 mm. In response to formalin-induced pain, single unit activities are robustly measured at the thalamus with electrodes whose vertical depth is adjusted by the microdrive under urethane anesthesia. In addition, the microdrive was efficient in detecting neural signals from mice that were moving freely. Thus, the present study suggests that the PZT-based microdrive could be an alternative for the efficient detection of neural signals from mice during behavioral states without any stress to the mice. (Some figures in this article are in colour only in the electronic version)

Long-Term Depression of Intrinsic Excitability Accompanied by Synaptic Depression in Cerebellar Purkinje Cells

Long-term depression (LTD) at the parallel fiber (PF)-to-cerebellar Purkinje cell (PC) synapse is implicated in the output of PCs, the sole output of the cerebellar cortex. In addition to synaptic plasticity, intrinsic excitability is also one of the components that determines PC output. Although long-term potentiation of intrinsic excitability (LTP-IE) has been suggested, it has yet to be investigated how PF–PC LTD modifies intrinsic excitability of PCs. Here, we show that pairing of the PF and climbing fiber (CF) for PF–PC LTD induction evokes LTD-IE in cerebellar PCs from male C57BL/6 mice. Interestingly, this intrinsic plasticity showed different kinetics from synaptic plasticity, but both forms of plasticity share Ca2+ signaling and protein kinase C pathway as their underlying mechanism. Although small-conductance Ca2+-activated K+ channels play important roles in LTP-IE, no direct implication has been found. After PF–PC LTD induction, neither the temporal summation of dendritic EPSP nor the power of spike frequency adaptation is changed, indicating that cerebellar LTD executes the information processing in a quantitative way without quality changes of synaptic integration and generation of output signals. Our results suggest that LTD-IE may have a synergistic effect with synaptic depression on the total net output of neurons by amplifying the modification of PF synaptic transmission. SIGNIFICANCE STATEMENT Although the output of Purkinje cells (PCs) is a critical component of cerebellum-dependent learning and memory, the changes of PC excitability when synaptic LTD occurs are unclear. Here, we show that the induction of PF–PC LTD evokes LTD-IE in PCs. Our observation complements previous intrinsic plasticity phenomenon of long-term potentiation of intrinsic excitability (LTP-IE), providing evidence for the idea that intrinsic plasticity has bidirectionality as synaptic plasticity. LTD-IE occurs together with synaptic LTD and both phenomena are dependent on the Ca2+ signaling pathway. Furthermore, our findings raise the prospect that this synaptic and intrinsic plasticity acts synergistically in PCs to modify neuronal activity in the same direction when learning occurs.

Influence of TiO2 on alpha case reaction of Al2O3 mould in Ti investment casting

Abstract Experiments were conducted to evaluate the alpha case reaction layer of Ti casting with four different mould materials: Al2O3, Al2O3+Ti, Al2O3+TiO2, and TiO2. Al2O3+Ti moulds were manufactured by a reaction between Al2O3 and Ti powder in air or vacuum. The results show that the Al2O3 mold exhibits an alpha case layer of ∼350 μm. The microstructural characterisation and surface hardness profiles of castings with Al2O3+Ti moulds indicated that the alpha case thickness decreased significantly to ∼45 μm. This difference was due to the presence of TiO2, which formed a TiO intermediate phase that acted as a diffusion barrier and hindered the alpha case reaction at the casting surface. In addition, Al2O3+TiO2 moulds were ineffective in alpha case reduction due to the unacceptable network between the TiO2 and binder.