Cell . . . How does whole hemp selectively affect the neurons of the cortex vertebral body?

One of the mysteries of general anesthesia (general anesthesia) written by Chen Wenqiang (postdoctoral of Harvard Medical School) is why general anesthesia can specifically inhibit the generation of consciousness by disrupting brain feedback signals, while feedforward signals and basic neural functions are not affected [1].previous studies have shown that general anesthesia can reduce the feedback signal of cortex (Fig. 1), and cortical vertebral neurons play a key role in this process, because cortical vertebral neurons have distal apical dendrite structure in L1 layer and can receive a large number of cortical feedback signals [2].therefore, it is an obvious hypothesis that general anesthesia may play a role by downregulating the distal apical dendrite structure of L5 vertebral neurons, which may be produced by regulating the coupling between the periapical component and the distal apical dendrite structure (Fig. 1).to answer this question, researchers from Humboldt University in Berlin (mototaka Suzuki and Matthew larkum, two authors of this paper) recently published an online journal "general anesthesia decouples cortical pyramid" in cell magazine Neurons' research paper, the feedback signal input to L1 cortex was simulated by photogenetics to study the effect of general anesthesia on cortical network.this study not only provides a new explanation of how general anesthesia selectively blocks feedback signals, but also suggests how conscious consciousness depends on the intercortical and cortical thalamic circuits.first of all, the researchers used photogenetics to induce the depolarization of the distal apical dendrite structure of the L5 vertebral neurons, simulating the feedback signals input to the L1 cortex.this method can produce continuous effects on dendrite structure, so as to study the effect of cell and network level under general anesthesia.the researchers used the L1 specific light projection device, μ periscope, so that the blue light can only irradiate the L1 layer of cortex, and then record the electrical signal of the L5 vertebral body.in addition, through the on / off of isoflurane anesthesia, researchers can control the awake / anesthetized state of experimental animals, and keep the experimental conditions of light supply and recording unchanged (Fig. 1).Figure 1. Cortical vertebral neurons mediate brain feedback signals. The researchers did not observe changes in the response of distal dendrites between awake and anesthetized states induced by photogenetic stimulation.however, the response of the L5 cortical soma was significantly dependent on the state of the brain (Fig. 2, left).the response of the cell body is divided into two parts: high frequency and low frequency, which are completely absent under anesthesia (Fig. 2, right).the incubation period of the first reaction of the cell body caused by light on the distal dendrite structure is very short (about 5.9 MS), indicating that there is a very good coupling between the distal dendrite and the cell body in the awake state.the researchers found that these effects did not depend on the variety of anesthetics, including isoflurane, Chloroacetone / tolbutazine, urethane, etc. these anesthetics have different molecular targets, which indicates that the coupling between the distal and proximal structures of vertebral neurons may be a broad target of anesthesia.interestingly, this state dependent coupling change of the brain can also be seen in other cortical regions, but the L2 / 3 vertebral neurons of the cortex do not show this dependence.interested readers can refer to fig.s2. Fig. 2. Different responses of dendrites and cell bodies stimulated by photogenetics depend on the state of the mice (awake or anesthetized). The question to be answered later is whether the action potential generated by the cell body is involved in the high-frequency response in the awake state.the researchers adopted two strategies: intracellular recording of single neuron near the cell body and multichannel extracellular recording in vitro (Fig. 3). both strategies demonstrated that the high frequency response in awake state came from the action potential of soma cells in L5 vertebral body neurons. Fig. 3. Intracellular and extracelluar recordings near the cell body were observed. Subsequently, the researchers found that anesthesia prevented the cytoplasmic action potential induced by dendritic depolarization, thus terminating the effective feedback input to the distal dendrite. so far, the coupling between dendrite and soma can be defined as the effect of dendrite depolarization on the action potential. so, what is the mechanism of the signal decoupling produced by the distal apical dendritic structure? Using a more sophisticated electrode recording method (50 micron recording interval), the researchers examined the characteristics of dendritic response and signal propagation along the apical dendrite under awake and anesthetized conditions. It was found that the dendritic signal can effectively transmit to the cell body to cause high-frequency response in awake state, while this transmission is significantly reduced in anesthesia state (Fig. 4). Fig. 4. The propagation of dendrite cytoplasmic signals is significantly blocked in the distal region. Another question to be answered is: how can various neurotransmitters and conditioning systems that affect neuronal activity change the state of the brain by affecting the characteristics of neurons? This problem can be studied by injecting tool drugs into the distal dendrites (Fig. 5). the researchers injected L-type calcium channel blockers, NMDA receptor blockers, acetylcholinergic blockers (ionic and metabolic) and adrenergic antagonists into the distal dendrites through the drug delivery catheter, which could significantly reduce the dendritic response. Only acetylcholine blockers could significantly reduce the soma response induced by the dendrites in the awake state. that is to say, blocking the metabolic acetylcholine receptor can remove the coupling between dendrite and soma of L5 vertebral neurons in awake state. Fig. 5. The tool drug study in this paper: injecting tool drugs into the apical dendrites to study the soma response. The last important question is, how does anesthesia affect the decoupling of the cortical thalamic loop? Because this paper mainly studies the somatosensory cortex, the higher thalamic nucleus corresponding to the cortex is the posterior median nucleus (POM), which has more projections to the L5 layer and L1 layer cortex, and some studies have shown that the thalamic projection can regulate the cortical state [3]. local injection of metabotropic glutamate receptor antagonists was found to significantly affect neuronal activity in the injection area and damage this coupling (Fig. 6). Figure 6. The role of the cortical thalamic loop in the dendrite soma coupling. The data in this paper show that the conscious state can activate the apical dendrites, thus producing the cell body action potential, which is manifested in the enhanced dendrite soma coupling. the main conclusion of this paper is summarized in Fig. 7 - the technical advantage of this paper lies in the selective activation of distal dendrites by using the limited light supply range of the μ periscope technology, avoiding the technical difficulties of control feedback connection. the characteristics of depolarization induced by photogenetic activation of the distal dendrites are very similar, but the responses on the L5 layer are significantly different. Similarly, the responses recorded in the responsive thalamic nuclei are also very different. in addition, metabotropic glutamate receptor blockers can block this coupling to the greatest extent. therefore, the phenomenon found in this paper not only explains why anesthetics can selectively block the signal of this distal dendrite, but also connects the two main theories of consciousness production at the cellular level. Fig. 7. A new theory of general anesthesia suggested in this paper. Link: plate maker: xiaoxianzi, Ref. 1. Mashour (2014). Top down mechanisms of anesthetic induced unconsciousness. Front. Syst. Neurosci. 8, 115.2. Larkum. (2013). A cellular mechanism for corticalassociations: an organizing principle for the cerebral cortex. Trends Neurosci. 36, 141-151.3. Llinas and Ribary (2001). Consciousness and the brain.The thalamocortical dialogue in health and disease. Ann. N Y Acad. Sci.929, 166-175.