Reza Lashgari

Behavioral and electrophysiological studies of chronic oral administration of L-type calcium channel blocker verapamil on learning and memory in rats

It has been shown that L-type voltage dependent calcium channels (VDCCs) have important role in learning and memory. In vivo and in vitro electrophysiological recordings of hippocampal neurons have demonstrated their involvement in long-term potentiation (LTP), which considers being one possible cellular mechanism underlying learning and memory. The long-term effect of VDCCs of hippocampal dentate gyrus (DG) so far on synaptic plasticity has not received much attention. In this study, the effect of chronic (60 days) oral administration of L-type calcium channel blocker verapamil on learning and memory and synaptic plasticity of hippocampal dentate gyrus in rats has been investigated. L-type calcium channel antagonist, verapamil chronically and orally at different doses (10, 20 and 50 mg/kg) was used to investigate learning and memory by passive avoidance learning. LTP in perforant-DG synapses was assessed (by either 200 or 400 Hz tetanization) in order to investigate long-term effect of verapamil on synaptic plasticity. In this case, field excitatory postsynaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. Our behavioral study has shown that chronic oral treatment of verapamil has no effect on learning whereas verapamil (50 mg/kg) decreased memory retrieval. Verapamil (20 and 50 mg/kg) inhibited EPSP-LTP induction at 400 Hz but not at 200 Hz tetanization. Furthermore, only verapamil (50mg/kg) decreased PS-LTP with respect to control group. These data suggest that 400 Hz LTP is required for activation of L-type VDCCs and it seems that verapamil is more effective on L-type calcium channels of DG dendrites than their soma.

Neuronal nonlinearity explains greater visual spatial resolution for darks than lights

Significance Light and dark stimuli are separately processed by ON and OFF channels in retina and thalamus. Although most textbooks assume that ON and OFF visual responses are relatively balanced throughout the visual system, recent studies have identified a pronounced overrepresentation of OFF responses in the cerebral cortex. This recent discovery resonates with Galileo and Helmholtz’s pioneering observations that visual spatial resolution is higher for darks than lights. In this paper, we demonstrate that these two seemingly separate findings are related and caused by a pronounced difference between ON and OFF luminance response functions, which most likely originates in photoreceptors. Therefore, asymmetric ON and OFF neural responses provide the neurophysiological explanation for an almost four-century-old puzzle dating back to Galileo. Astronomers and physicists noticed centuries ago that visual spatial resolution is higher for dark than light stimuli, but the neuronal mechanisms for this perceptual asymmetry remain unknown. Here we demonstrate that the asymmetry is caused by a neuronal nonlinearity in the early visual pathway. We show that neurons driven by darks (OFF neurons) increase their responses roughly linearly with luminance decrements, independent of the background luminance. However, neurons driven by lights (ON neurons) saturate their responses with small increases in luminance and need bright backgrounds to approach the linearity of OFF neurons. We show that, as a consequence of this difference in linearity, receptive fields are larger in ON than OFF thalamic neurons, and cortical neurons are more strongly driven by darks than lights at low spatial frequencies. This ON/OFF asymmetry in linearity could be demonstrated in the visual cortex of cats, monkeys, and humans and in the cat visual thalamus. Furthermore, in the cat visual thalamus, we show that the neuronal nonlinearity is present at the ON receptive field center of ON-center neurons and ON receptive field surround of OFF-center neurons, suggesting an origin at the level of the photoreceptor. These results demonstrate a fundamental difference in visual processing between ON and OFF channels and reveal a competitive advantage for OFF neurons over ON neurons at low spatial frequencies, which could be important during cortical development when retinal images are blurred by immature optics in infant eyes.

Faster Thalamocortical Processing for Dark than Light Visual Targets

ON and OFF visual pathways originate in the retina at the synapse between photoreceptor and bipolar cells. OFF bipolar cells are shorter in length and use receptors with faster kinetics than ON bipolar cells and, therefore, process information faster. Here, we demonstrate that this temporal advantage is maintained through thalamocortical processing, with OFF visual responses reaching cortex ∼3–6 ms before ON visual responses. Faster OFF visual responses could be demonstrated in recordings from large populations of cat thalamic neurons representing the center of vision (both X and Y) and from subpopulations making connection with the same cortical orientation column. While the OFF temporal advantage diminished as visual responses reached their peak, the integral of the impulse response was greater in OFF than ON neurons. Given the stimulus preferences from OFF and ON channels, our results indicate that darks are processed faster than lights in the thalamocortical pathway.

EFFECT OF REVERSIBLE INACTIVATION OF LOCUS CERULEUS ON SPATIAL REFERENCE AND WORKING MEMORY

The locus coeruleus (LC) is the largest source of norepinephrine (NE) in the prefrontal cortex and the hippocampus, influencing the cognitive functions of these areas. All previous studies have studied the role of the LC-NE system on learning and memory using the irreversible lesion technique, employing either electrocoagulation or excitotoxins. However, the reversible functional inactivation of LC by means of stereotaxic local microinjection of lidocaine could measure the phases of memory processing (acquisition, consolidation and retention) without any interference with the other cognitive functions of the same structure either during earlier or later phases of the same process. The aim of this study is to investigate LC involvement in spatial reference and working memory by inducing bilateral pre-training, post-training and pre-retrieval lidocaine functional inactivation using the Morris water maze task. The reversible inactivation of LC was applied at different stages of spatial memory formation: (1) immediately before the training sessions to determine the effects on acquisition of the both reference and working memory; (2) immediately after the training session to evaluate effects on both spatial memory consolidation and retention of working memory; and (3) immediately before the 24 h retention session to analyze the effects on the retrieval process of reference memory. Our results indicate that the bilateral reversible inactivation of LC significantly impaired the acquisition of reference and working memory, while it had no effect on consolidation and/or retention of such memories in the Morris water maze (MWM) task. Therefore, the noradrenergic system of the LC may play a more important role in acquisition than in consolidation and retrieval of spatial memory in wistar rats.

Neuronal and perceptual differences in the temporal processing of darks and lights

Visual information is mediated by two major thalamic pathways that signal light decrements (OFF) and increments (ON) in visual scenes, the OFF pathway being faster than the ON. Here, we demonstrate that this OFF temporal advantage is transferred to visual cortex and has a correlate in human perception. OFF-dominated cortical neurons in cats responded ∼3 ms faster to visual stimuli than ON-dominated cortical neurons, and dark-mediated suppression in ON-dominated neurons peaked ∼14 ms faster than light-mediated suppression in OFF-dominated neurons. Consistent with the neuronal differences, human observers were 6-14 ms faster at detecting darks than lights and better at discriminating dark than light flickers. Neuronal and perceptual differences both vanished if backgrounds were biased toward darks. Our results suggest that the cortical OFF pathway is faster than the ON pathway at increasing and suppressing visual responses, and these differences have parallels in the human visual perception of lights and darks.

Effects of treadmill running on short-term pre-synaptic plasticity at dentate gyrus of streptozotocin-induced diabetic rats

Previous studies indicated that diabetes mellitus leads to impairments in hippocampal synaptic plasticity and defects in learning and memory. Although diabetes affects synaptic transmission in the hippocampus through both pre- and post-synaptic influences, it is not clear if the defects are pre- or post-synaptic or both; and whether these are prevented by running. The aim of this study was to evaluate the effects of treadmill running on short-term plasticity in inhibitory interneurons in the dentate gyrus of STZ-induced diabetic rats. Experimental groups were the control-rest group, the control-exercise group, the diabetes-rest group and the diabetes-exercise group (n=6 for each experimental group). The exercise program was moderate exercise consisting of treadmill running at 17 m/min and 0-degree inclination for 40 min/day, 7 days/week, for 12 weeks. The paired pulse paradigm was used to stimulate the perforant pathway and field excitatory post-synaptic potentials (fEPSP) were recorded in dentate gyrus (DG). In the diabetic-rest group paired pulse facilitation was significantly increased comparing to the control-rest group. However, there were no differences between responses of the control-exercise and diabetes-exercise groups compared to the control-rest group. The present results suggest that the pre-synaptic component of synaptic plasticity in the dentate gyrus is affected under diabetic conditions and that treadmill running prevents this effect. The data support the possibility that alterations in transmission may account, in part, for learning and memory deficits induced in diabetes, and that treadmill running is helpful in alleviating the neural complications of diabetes mellitus.

The role of GABAergic transmission in the dentate gyrus on acquisition, consolidation and retrieval of an inhibitory avoidance learning and memory task in the rat.

The hippocampal GABAergic interneurons are responsible for controlling the input of large principal cell populations, and they thereby determine the oscillatory discharge patterns and synaptic plasticity in the hippocampus. Such oscillations within neuronal systems serve various complex functions, such as perception, cognition, plasticity and memory. The aim of this study is to define the function of GABAergic synaptic transmission in the dentate gyrus (DG) of the hippocampus in the different stages of inhibitory avoidance (IA) learning and memory in the rat. Two cannulae were implanted above the hippocampal DG. Then the rats were trained on a step-through IA learning task. Each rat received intra-DG injection of picrotoxin (PTX) or saline before training, after training or before the retrieval test. The results show that post-training injection of PTX impaired the IA memory. On the other hand, pre-training and pre-retrieval injection of PTX had no significant effect on the IA activity. Therefore, it seems that GABAergic transmission in the DG is involved in the consolidation step (but not in the acquisition and retrieval steps) of the IA task by controlling the input to the principal cells.

RESPONSE PROPERTIES OF LOCAL FIELD POTENTIALS AND NEIGHBORING SINGLE NEURONS IN AWAKE PRIMARY VISUAL CORTEX

Recordings from local field potentials (LFPs) are becoming increasingly common in research and clinical applications, but we still have a poor understanding of how LFP stimulus selectivity originates from the combined activity of single neurons. Here, we systematically compared the stimulus selectivity of LFP and neighboring single-unit activity (SUA) recorded in area primary visual cortex (V1) of awake primates. We demonstrate that LFP and SUA have similar stimulus preferences for orientation, direction of motion, contrast, size, temporal frequency, and even spatial phase. However, the average SUA had 50 times better signal-to-noise, 20% higher contrast sensitivity, 45% higher direction selectivity, and 15% more tuning depth than the average LFP. Low LFP frequencies (<30 Hz) were most strongly correlated with the spiking frequencies of neurons with nonlinear spatial summation and poor orientation/direction selectivity that were located near cortical current sinks (negative LFPs). In contrast, LFP gamma frequencies (>30 Hz) were correlated with a more diverse group of neurons located near cortical sources (positive LFPs). In summary, our results indicate that low- and high-frequency LFP pool signals from V1 neurons with similar stimulus preferences but different response properties and cortical depths.

Columnar organization of spatial phase in visual cortex

Images are processed in the primary visual cortex by neurons that encode different stimulus orientations and spatial phases. In primates and carnivores, neighboring cortical neurons share similar orientation preferences, but spatial phases were thought to be randomly distributed. We discovered a columnar organization for spatial phase in cats that shares similarities with the columnar organization for orientation. For both orientation and phase, the mean difference across vertically aligned neurons was less than one-fourth of a cycle. Cortical neurons showed threefold more diversity in phase than orientation preference; however, the average phase of local neuronal populations was similar through the depth of layer 4. We conclude that columnar organization for visual space is not only defined by the spatial location of the stimulus, but also by absolute phase. Taken together with previous findings, our results suggest that this phase-visuotopy is responsible for the emergence of orientation maps.

Treadmill running improves long-term potentiation (LTP) defects in streptozotocin-induced diabetes at dentate gyrus in rats.

OBJECTIVES It has been demonstrated that exercise has neuroprotective effects in the central nervous system (CNS), especially in hippocampus. Previous studies have indicated that diabetes mellitus affects synaptic plasticity in the hippocampus leading to impairments in learning and memory. The aim of this study was to evaluate the effects of treadmill running on synaptic plasticity at dentate gyrus (DG) of streptozotocin-induced diabetic rats. STUDY DESIGN Experimental groups were the control, the diabetes and the diabetes-exercise groups. Long-term potentiation (LTP) in perforant path-DG synapses was assessed (by 400Hz tetanization) in order to investigate the effect of exercise on synaptic plasticity. Field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude were measured. RESULTS With respect to the control group, fEPSP were significantly decreased in the diabetes group. However, there were no differences between responses of the diabetes-exercise group and the control. CONCLUSION The present results suggest that LTP induction in the dentate gyrus is affected under diabetic conditions and that treadmill running prevents these effects. The data suggest that treadmill running protect against diabetes-induced decrease of learning ability and memory function of the hippocampus.