Functional hemidecortication by spreading depression or by focal epileptic discharge disrupts spatial memory in rats

The importance of neocortex for the acquisition and retrieval of the water tank navigation task has been examined in 110 hooded rats. The animals were trained to swim to a small (10 cm in diameter) submersed platform 1 cm below the surface of a large pool (120 cm in diameter) of opaque water. In Experiment 1, naive rats with unilateral cortical spreading depression (SD) elicited by application of a filter paper soaked with 25% KC1 on one hemicortex were unable to find the platform during 1 min in about 50% of the 12 acquisition trials. The performance of functionally hemidecorticated rats did not improve after a single trial with the intact brain, but escape latencies were significantly shortened in rats given 2,6 or 60 pretraining trials with intact brain. Even in the overtrained rats escape latencies under unilateral SD were significantly longer (14 sec) than in intact rats after 12 acquisition trials (5 sec). In Experiment 2, development of an epileptic focus established by local penicillin application onto the exposed cortical surface was electrophysiologically monitored. Regular interictal discharge (0.2 to 0.5 Hz) disrupted acquisition of the navigation task and interfered to a lesser degree with performance in rats given 12 and 36 pretraining trials with the intact brain. The occipital foci were more disruptive than the frontoparietal ones. Performance recovered with cessation of the epileptic discharge. It is concluded that spatial memory mediating navigation in the water tank task requires coordinated activity of both cerebral hemispheres.     

Small-scale spatial cognition in pigeons

Roberts and Van Veldhuizen's [Roberts, W.A., Van Veldhuizen, N., 1985. Spatial memory in pigeons on the radial maze. J. Exp. Psychol.: Anim. Behav. Proc. 11, 241-260] study on pigeons in the radial maze sparked research on landmark use by pigeons in lab-based tasks as well as variants of the radial-maze task. Pigeons perform well on open-field versions of the radial maze, with feeders scattered on the laboratory floor. Pigeons can also be trained to search precisely for buried food. The search can be based on multiple landmarks, but is sometimes controlled by just one or two landmarks, with the preferred landmarks varying across individuals. Findings are similar in landmark-based searching on a computer monitor and on a lab floor, despite many differences between the two kinds of tasks. A number of general learning principles are found in landmark-based searching, such as cue competition, generalization and peak shift, and selective attention. Pigeons also learn the geometry of the environment in which they are searching. Neurophysiological studies have implicated the hippocampal formation (HF) in avian spatial cognition, with the right hippocampus hypothesized to play a more important role in the spatial recognition of goal locations. Most recently, single-cell recording from the pigeon's hippocampal formation has revealed cells with different properties from the classic 'place' cells of rats, as well as differences in the two sides of the hippocampus.     

The role of spreading depression, spreading depolarization and spreading ischemia in neurological disease

The term spreading depolarization describes a wave in the gray matter of the central nervous system characterized by swelling of neurons, distortion of dendritic spines, a large change of the slow electrical potential and silencing of brain electrical activity (spreading depression). In the clinic, unequivocal electrophysiological evidence now exists that spreading depolarizations occur abundantly in individuals with aneurismal subarachnoid hemorrhage, delayed ischemic stroke after subarachnoid hemorrhage, malignant hemispheric stroke, spontaneous intracerebral hemorrhage or traumatic brain injury. Spreading depolarization is induced experimentally by various noxious conditions including chemicals such as potassium, glutamate, inhibitors of the sodium pump, status epilepticus, hypoxia, hypoglycemia and ischemia, but it can can also invade healthy, naive tissue. Resistance vessels respond to it with tone alterations, causing either transient hyperperfusion (physiological hemodynamic response) in healthy tissue or severe hypoperfusion (inverse hemodynamic response, or spreading ischemia) in tissue at risk for progressive damage, which contributes to lesion progression. Therapies that target spreading depolarization or the inverse hemodynamic response may potentially treat these neurological conditions.     

Physiological studies of cortical spreading depression

Cortical spreading depression (CSD) produces propagating waves of transient neuronal hyperexcitability followed by depression. CSD is initiated by K+ release following neuronal firing or electrical, mechanical or chemical stimuli. A triphasic (30-50 s) cortical potential transient accompanies localized transmembrane redistributions of K+, glutamate, Ca2+, Na+, Cl- and H+. Accumulated K+ in the restricted interstitial space can cause both further neuronal depolarisation and inward movement of K+ into astrocytes that buffers this increased extracellular K+ concentration ([K+])o. However, astrocyte interconnections may then propagate the CSD wave by K+ liberation through an opening of remote K+ channels by volume, Ca2+ or N-methyl-D-aspartate receptor activation. Changes in cerebral blood volume and in apparent water diffusion co-efficient (ADC) accompanying CSD were first studied using magnetic resonance imaging (MRI) in whole lissencephalic brains. Diffusion-weighted echoplanar imaging in gyrencephalic brains went on to demonstrate CSD features that paralleled classical migraine aura. The ADC activity persisted minutes/hours post KCl stimulus. Pixelwise analyses distinguished single primary events and multiple, spatially restricted, slower propagating, secondary events whose detailed features varied with the nature of the originating stimulus. These ADC changes varied reciprocally with T2*-weighted (i.e. referring to spin-spin relaxation times) waveforms reflecting local blood flow. There followed prolonged decreases in cerebral blood flow culminating in late cerebrovascular changes blocked by the antimigraine agent sumatriptan. CSD phenomena have possible translational significance for human migraine aura and other cerebral pathologies such as the peri-infarct depolarisation events that follow ischaemia and brain injury.     

解码大脑的空间方位认知

在过去的几十年间,与大脑空间方位认知功能相关的位置细胞、网格细胞、头朝向细胞和边界细胞陆续被发现,它们共同构成了大脑内部的导航定位系统。O'Keefe教授和Moser夫妇这三位科学家也正是由于发现了位置细胞和网格细胞,而共同获得了2014年的诺贝尔生理学或医学奖。     

Carnitine palmitoyltransferase 1C: From cognition to cancer

Carnitine palmitoyltransferase 1 (CPT1) C was the last member of the CPT1 family of genes to be discovered. CPT1A and CPT1B were identified as the gate-keeper enzymes for the entry of long-chain fatty acids (as carnitine esters) into mitochondria and their further oxidation, and they show differences in their kinetics and tissue expression. Although CPT1C exhibits high sequence similarity to CPT1A and CPT1B, it is specifically expressed in neurons (a cell-type that does not use fatty acids as fuel to any major extent), it is localized in the endoplasmic reticulum of cells, and it has minimal CPT1 catalytic activity with l-carnitine and acyl-CoA esters. The lack of an easily measurable biological activity has hampered attempts to elucidate the cellular and physiological role of CPT1C but has not diminished the interest of the biomedical research community in this CPT1 isoform. The observations that CPT1C binds malonyl-CoA and long-chain acyl-CoA suggest that it is a sensor of lipid metabolism in neurons, where it appears to impact ceramide and triacylglycerol (TAG) metabolism. CPT1C global knock-out mice show a wide range of brain disorders, including impaired cognition and spatial learning, motor deficits, and a deregulation in food intake and energy homeostasis. The first disease-causing CPT1C mutation was recently described in humans, with Cpt1c being identified as the gene causing hereditary spastic paraplegia. The putative role of CPT1C in the regulation of complex-lipid metabolism is supported by the observation that it is highly expressed in certain virulent tumor cells, conferring them resistance to glucose- and oxygen-deprivation. Therefore, CPT1C may be a promising target in the treatment of cancer. Here we review the molecular, biochemical, and structural properties of CPT1C and discuss its potential roles in brain function, and cancer.     

Retinal spreading depression and the extracellular milieu

We used isolated chick retina in vitro to study the participation of the extracellular milieu in the occurrence and propagation of spreading depression. The propagation was followed by visual observation or microphotometry and the ionic changes in the extracellular compartment were recorded with double-barreled ion-selective microelectrodes. The front of the spreading wave is accompanied by increased light scattering in the tissue and by decrease of Cl-, Na+, and Ca2+, increase of K+, and an alkaline-acid shift in the extracellular space, concomitant with the slow voltage changes characteristic of the wave. As the spread is related to the chemical steady-state of the extracellular milieu, the velocity of propagation is influenced by a balanced interplay of the chemical constituents of the superfusing solution, e.g., K+, HCO-3, and glucose facilitate, while Cl- and Mg2+ hinder the wave. Steady-state alterations induced by physical factors (temperature) or related to experimental conditions (speed and direction of superfusate flow) change markedly the velocity of propagation. Generally the procedures that cause increase of velocity augment the susceptibility of the preparation to the reaction and eventually may trigger it. Propagated spreading depression is considered as a chemical diffusion reaction pervading more intensively the inner plexiform layer of the retina.     

Rhythmic metrazol activity and cortical spreading depression

The incidence of segments of rhythmic metrazol activity (RMA) in cortical leads and in the thalamus and hippocampus was studied in acute experiments on nine male albino laboratory rats. First of all we studied activity after administering metrazol in an i.p. dose of 50 mg/kg, without any further treatment, and then, after a control recording, we induced cortical spreading depression and observed its effect on the incidence and synchronization of RMA in the individual leads. We came to the conclusion that the thalamus is incapable of isolated production of RMA. The cortex is able to produce RMA without participation by the studied structures of the specific thalamus and hippocampus; RMA probably originates in the cortex itself. Generalization is impaired, but not eliminated, by a cortical block. The hippocampus independently produces another type of rhythmic activity.