Shogo Soma

Cholinergic modulation of response gain in the primary visual cortex of the macaque.

ACh modulates neuronal activity throughout the cerebral cortex, including the primary visual cortex (V1). However, a number of issues regarding this modulation remain unknown, such as the effect and its function and the receptor subtypes involved. To address these issues, we combined extracellular single-unit recordings and microiontophoretic administration of ACh and measured V1 neuronal responses to drifting sinusoidal grating stimuli in anesthetized macaque monkeys. ACh was found to have mostly facilitatory effects on the visual responses, although some cases of suppressive effects were also seen. To assess the functional role of ACh, we further examined how ACh modulates the stimulus contrast-response function, finding that the response gain increased with the facilitatory effect. The response facilitation was completely or strongly blocked by atropine (At), a muscarinic ACh receptor (mAChR) antagonist, in almost all neurons (96% of cells), whereas any residual effect after At administration was fully removed by mecamylamine, a nicotinic AChR (nAChR) antagonist, suggesting a predominant role for mAChRs in this mechanism. Furthermore, we found no laminar distribution bias for the facilitatory modulation, although the relative contribution of mAChRs was smaller in layer 4C than in other layers. The suppressive effect was blocked completely by At. These results demonstrate that ACh plays an important role in visual information processing in V1 by controlling the response gain via mAChRs across all cortical layers and via nAChRs, mainly in layer 4C.

Cholinergic modulation of response gain in the rat primary visual cortex

Acetylcholine (ACh) is known to modulate neuronal activity in the rodent primary visual cortex (V1). Although cholinergic modulation has been extensively examined in vitro, far less is understood regarding how ACh modulates visual information processing in vivo. We therefore extracellularly recorded visual responses to drifting sinusoidal grating stimuli from V1 of anesthetized rats and tested the effects of ACh administered locally by microiontophoresis. ACh exerted response facilitation or suppression in individual neurons across all cortical layers without any laminar bias. We assessed ACh effects on the stimulus contrast-response function, finding that ACh increased or decreased the response to varying stimulus contrasts in proportion to the magnitude of the control response without changing the shape of the original contrast-response function, which describes response gain control but not contrast gain control. Our results indicate that ACh serves as a gain controller in the visual cortex of rodents.

Modulation-Specific and Laminar-Dependent Effects of Acetylcholine on Visual Responses in the Rat Primary Visual Cortex

Acetylcholine (ACh) is secreted from cholinergic neurons in the basal forebrain to regions throughout the cerebral cortex, including the primary visual cortex (V1), and influences neuronal activities across all six layers via a form of diffuse extrasynaptic modulation termed volume transmission. To understand this effect in V1, we performed extracellular multi-point recordings of neuronal responses to drifting sinusoidal grating stimuli from the cortical layers of V1 in anesthetized rats and examined the modulatory effects of topically administered ACh. ACh facilitated or suppressed the visual responses of individual cells with a laminar bias: response suppression prevailed in layers 2/3, whereas response facilitation prevailed in layer 5. ACh effects on the stimulus contrast-response function showed that ACh changes the response gain upward or downward in facilitated or suppressed cells, respectively. Next, ACh effects on the signal-to-noise (S/N) ratio and the grating-phase information were tested. The grating-phase information was calculated as the F1/F0 ratio, which represents the amount of temporal response modulation at the fundamental frequency (F1) of a drifting grating relative to the mean evoked response (F0). In facilitated cells, ACh improved the S/N ratio, while in suppressed cells it enhanced the F1/F0 ratio without any concurrent reduction in the S/N ratio. These effects were predominantly observed in regular-spiking cells, but not in fast-spiking cells. Electrophysiological and histological findings suggest that ACh promotes the signaling of grating-phase information to higher-order areas by a suppressive effect on supragranular layers and enhances feedback signals with a high S/N ratio to subcortical areas by a facilitatory effect on infragranular layers. Thus, ACh distinctly and finely controls visual information processing in a manner that is specific for the modulation and cell type and is also laminar dependent.

Cholinesterase inhibitor, donepezil, improves visual contrast detectability in freely behaving rats.

Acetylcholine (ACh) modulates neuronal activities in extensive brain regions to play an essential role in various brain functions including attention, learning and memory, and cognition. Although ACh is known to modulate information processing in the primary visual cortex (V1) in many species including rodent, its functional role in visual ability has remained unknown. We examined whether and how ACh influences behavioral contrast detectability in rat. The detectability was assessed as the contrast sensitivity (CS) to a grating stimulus. Measurements were performed in a two-alternative forced-choice task combined with a staircase method in freely behaving rats. The contrast sensitivity function of rats under the no drug condition showed a low-pass spatial frequency (SF) tuning peaking at 0.1 cycles/degree (cpd) of SF (SF(peak)) that bottomed at 0.5 cpd (SF(bottom)), which was sensitive to the stimulus size, but to neither the temporal frequency nor orientation of the stimulus. The stimulus size was correlated with the CS only at the low SF range. The effect of donepezil on the size- and SF-dependency of the CS was examined using three stimulus conditions: an easy detectability condition with large grating at SF(peak), a difficult detectability condition with small grating at SF(peak), and an upper limit SF condition with large grating at SF(bottom). Donepezil improved the CS at SF(peak), especially in the difficult detectability condition. Therefore, we conclude that ACh plays an important role in enhancing behavioral CS at sensitive SF ranges, but not in improving the upper limit of SF.

Blockade of muscarinic receptors impairs the retrieval of well-trained memory.

Acetylcholine (ACh) is known to play an important role in memory functions, and its deficit has been proposed to cause the cognitive decline associated with advanced age and Alzheimers disease (the cholinergic hypothesis). Although many studies have tested the cholinergic hypothesis for recently acquired memory, only a few have investigated the role of ACh in the retrieval process of well-trained cognitive memory, which describes the memory established from repetition and daily routine. To examine this point, we trained rats to perform a two-alternative forced-choice visual detection task. Each trial was started by having the rats pull upward a central-lever, which triggered the presentation of a visual stimulus to the right or left side of the display monitor, and then pulling upward a stimulus-relevant choice-lever located on both sides. Rats learned the task within 10 days, and the task training was continued for a month. Task performance was measured with or without systemic administration of a muscarinic ACh receptor (mAChR) antagonist, scopolamine (SCOP), prior to the test. After 30 min of SCOP administration, rats stopped manipulating any lever even though they explored the lever and surrounding environment, suggesting a loss of the task-related associative memory. Three hours later, rats were recovered to complete the trial, but the rats selected the levers irrespective of the visual stimulus, suggesting they remembered a series of lever-manipulations in association with a reward, but not association between the reward and visual stimulation. Furthermore, an m1-AChR, but not nicotinic AChR antagonist caused a similar deficit in the task execution. SCOP neither interfered with locomotor activity nor drinking behavior, while it influenced anxiety. These results suggest that the activation of mAChRs at basal ACh levels is essential for the recall of well-trained cognitive memory.

Efficient training protocol for rapid learning of the two-alternative forced-choice visual stimulus detection task.

The potential of genetically engineered rodent models has accelerated demand for training procedures of behavioral tasks. Such training is generally time consuming and often shows large variability in learning speed between animals. To overcome these problems, we developed an efficient and stable training system for the two‐alternative forced‐choice (2AFC) visual stimulus detection task for freely behaving rodents. To facilitate the task learning, we introduced a spout‐lever as the operandum and a three‐step training program with four ingenuities: (1) a salient stimulus to draw passive attention, (2) a reward‐guaranteed trial to keep motivation, (3) a behavior‐corrective trial, and (4) switching from a reward‐guaranteed trial to a nonguaranteed one to correct behavioral patterns. Our new training system realizes 1‐week completion of the whole learning process, during which all rats were able to learn effortlessly the association between (1) lever‐manipulation and reward and (2) visual stimulus and reward in a step‐by‐step manner. Thus, our new system provides an effective and stable training method for the 2AFC visual stimulus detection task. This method should help accelerate the move toward research bridging the visual functions measured in behavioral tasks and the contributing specific neurons/networks that are genetically manipulated or optically controlled.

Noradrenaline Improves Behavioral Contrast Sensitivity via the β-Adrenergic Receptor.

Noradrenaline (NA) is released from the locus coeruleus in the brainstem to almost the whole brain depending on the physiological state or behavioral context. NA modulates various brain functions including vision, but many questions about the functional role of its effects and mechanisms remain unclear. To explore these matters, we focused on three questions, 1) whether NA improves detectability of a behavior-relevant visual stimulus, 2) which receptor subtypes contribute to the NA effects, and 3) whether the NA effects are specific for visual features such as spatial frequency (SF). We measured contrast sensitivity in rats by a two-alternative forced choice visual detection task and tested the effects of NA receptor blockers in three SF conditions. Propranolol, a β-adrenergic receptor inhibitor, significantly decreased contrast sensitivity, but neither prazosin nor idazoxan, α1- and α2-adrenergic receptor inhibitors, respectively, had an effect. This β blocker effect was observed only at optimal SF. These results indicate that endogenous NA enhances visual detectability depending on stimulus spatial properties via mainly β-adrenergic receptors.

Discretion for behavioral selection affects development of habit formation after extended training in rats

As training progresses, animals show a transition from goal-dependent behavior to goal-independent behavior (habitual responses). Habit formation is influenced by several factors, including the amount of training and action-outcome contingency. However, it remains unknown whether and how discretion for behavioral selection influences habit formation. To this end, we trained male rats in two types of two-alternative forced-choice task: visual association and nonvisual association tasks. In the first type of task, rats learned the association between reward and a visual cue, the position of which was randomly changed per trial so that rats had to make a judgmental decision about which choice delivered the reward in each trial (discreet judgment group); in the second type of task, the rats learned that a reward was delivered after either choice following task initiation (uncontrolled judgment group). To test the sensitivity to contingency manipulation, the extinction tests were conducted in short- and long-term trained groups, with the result that the overtrained rats in the uncontrolled judgment group, but not the other three groups, showed less sensitivity. To further investigate the reward sensitivity in the long-term trained groups from another perspective, we continuously and periodically altered the reward size for each trial. The rats of the discreet judgment group changed intertrial intervals depending on reward size, while this tendency was weaker in the uncontrolled judgment group. These results suggest that discreet judgment maintained goal-directed rat behavior, whereas uncontrolled judgment led to the development of habit-like behavior.

Receptive field properties of cat perigeniculate neurons correlate with excitatory and inhibitory connectivity to LGN relay neurons

The cat perigeniculate nucleus (PGN) is a visual sector of the thalamic reticular nucleus that consists of GABAergic neurons. It receives excitatory axon-collateral input from relay neurons of the dorsal lateral geniculate nucleus (LGN) to which it provides inhibitory input. Thus, it is usually argued that the PGN works as feedback inhibition to the LGN. At the single neuron level, however, this circuit can also provide lateral inhibition. Which inhibition dominates in the visual circuit of the thalamus has yet to be well characterized. In this study, we conducted cross-correlation analysis of single spike trains simultaneously recorded from PGN and LGN neurons in anesthetized cats. For 12 pairs of functionally connected PGN and LGN neurons with overlapped receptive fields (RF), we quantitatively compared RF properties including the spatial frequency (SF) and temporal frequency (TF) tunings of each neuron. We found the SF and TF tunings of PGN neurons and LGN neurons were similar when there was only excitatory input from the LGN neuron to the PGN neuron, but different when the PGN neuron returned inhibitory inputs back, suggesting the circuit between PGN and LGN neurons works as lateral inhibition for these properties.

Interaction between the lateral geniculate nucleus and the perigeniculate nucleus of the cat

The perigeniculate nucleus (PGN) is a layer of inhibitory GABAergic neurons lying over the dorsal surfaces of the lateral geniculate nucleus (LGN). It receives axon-collateral input from the principal cells of LGN and axon-collaterals of cortico-geniculate projections. PGN neuron sends back inhibitory projection to the LGN. It is known that these projections are organized in retinotopic manner. However, little is known about the relationship between visual receptive field properties of the PGN and LGN neurons, which are connected each other. To explore this point, we conducted a crosscorrelation analysis of single neuronal activity simultaneously recorded from the PGN and LGN neurons in anesthetized cats. For 15 pairs of functionally connected PGN and LGN neurons, we compared the receptive field properties, such as the spatial frequency tuning and temporal frequency tuning, of each neuron. Correlated firings were observed only in neuron pairs whose receptive fields were partially or entirely overlapped. We found a pattern of connection between these neurons, that is, the receptive field properties of the PGN neurons and the LGN neurons are similar when there is only excitatory connection from LGN to PGN (4 pairs), but different when the PGN neurons send inhibitory inputs to the LGN neurons (8 pairs). We also found that the inhibitory input from PGN neuron serves for sharpening the orientation selectivity of LGN neuron, which shows the orientation preference different from that of PGN neuron. These results suggest the inhibitory role of PGN neurons on the elaboration of the receptive field properties of LGN neurons.