Pharmacology of cortical inhibition

1. We have studied the effects of various pharmacological agents on the cortical inhibitory process described in the previous two papers (Krnjevi?, Randi? & Straughan, 1966a, b); the drugs were mostly administered directly by iontophoresis from micropipettes and by systemic injection (I.V.).2. Strychnine given by iontophoresis or by the application of a strong solution to the cortical surface potentiated excitatory effects, but very large iontophoretic doses also depressed neuronal firing. Subconvulsive and even convulsive systemic doses had little or no effect at the cortical level. There was no evidence, with any method of application, that strychnine directly interferes with the inhibitory process.3. Tetanus toxin, obtained from two different sources and injected into the cortex 12-48 hr previously, also failed to block cortical inhibition selectively. As with strychnine, there was some evidence of increased responses to excitatory inputs.4. Other convulsant drugs which failed to block cortical inhibition included picrotoxin, pentamethylene tetrazole, thiosemicarbazide, longchain omega-amino acids and morphine.5. The inhibition was not obviously affected by cholinomimetic agents or by antagonists of ACh.6. alpha- and beta-antagonists of adrenergic transmission were also ineffective.7. Cortical inhibition was fully developed in the presence of several general anaesthetics, including ether, Dial, pentobarbitone, Mg and chloralose. A temporary reduction in inhibition which is sometimes observed after systemic doses of pentobarbitone, is probably secondary to a fall in blood pressure.8. Several central excitants such as amphetamine, caffeine and lobeline also failed to show any specific antagonistic action on cortical inhibition.9. In view of the possibility that GABA is the chemical agent mediating cortical inhibition, an attempt was made to find a selective antagonist of its depressant action on cortical neurones. None of the agents listed above, nor any other of the substances tested, were able to block this action.10. It was concluded that cortical inhibition differs from spinal inhibition in its pharmacological properties; and that our observations are consistent with the possibility that GABA is the cortical inhibitory transmitter.     

Genetic influences on latent inhibition

The present study examined the development of latent inhibition in a number of inbred strains of mice. C57BL/6J, DBA/2J, C3H/Ibg, BALB/cByJ, A/J, CBA/J, 129/SvevTac, 129/SvJ, and AKR/J mice were screened for the development of latent inhibition. The latent inhibition paradigm involved 1 day of either 40 preexposures to the conditioned stimulus (CS) or no preexposure. On the following training day, the CS was twice paired with a shock unconditioned stimulus (US). On a subsequent test day, the strength of the CS-US association was measured. Mice preexposed to the CS should show a weaker CS-US association, which would reflect development of latent inhibition. Significant between-strain differences existed. The 129/Svev, C57BL/6, BALB/cByJ, AKR, and DBA/2 mice developed latent inhibition, but 129/SvJ, CBA, A, and C3H mice did not. Thus, genetic variance contributes to variability in the development of latent inhibition.     

Rapid learning in cortical coding of visual scenes

Experience-dependent plasticity in adult visual cortex is believed to have important roles in visual coding and perceptual learning. Here we show that repeated stimulation with movies of natural scenes induces a rapid improvement in response reliability in cat visual cortex, whereas stimulation with white noise or flashed bar stimuli does not. The improved reliability can be accounted for by a selective increase in spiking evoked by preferred stimuli, and the magnitude of improvement depends on the sparseness of the response. The increase in reliability persists for at least several minutes in the absence of further movie stimulation. During this period, spontaneous spiking activity shows detectable reverberation of the movie-evoked responses. Thus, repeated exposure to natural stimuli not only induces a rapid improvement in cortical response reliability, but also leaves a 'memory trace' in subsequent spontaneous activity.     

The forgetting of stimulus attributes in latent inhibition

Numerous studies have demonstrated that the forgetting of stimulus attributes is a common occurrence; that is, organisms forget the specific characteristics of training stimuli over long retention intervals, while retaining general information of the training stimuli themselves. However, most studies have examined this effect after a learning episode, and there have been virtually no accounts to test whether the forgetting of attributes occurs for stimuli presented prior to training. Therefore, this experiment was designed to test that possibility, and it examined whether the forgetting of stimulus attributes occurred prior to training for the flavor stimulus in a conditioned taste aversion (CTA) procedure. Specifically, a latent inhibition (LI) procedure was used to measure the extent of forgetting for a pre-exposed flavor over short and long retention intervals. The results indicate that rats forgot the specific characteristics of the flavor stimulus (CS) while retaining memory for pre-exposure sessions over a long retention interval. That is, subjects pre-exposed and conditioned with different concentrations of sucrose showed no LI effect with a 1-day delay between pre-exposure and training, but demonstrated a generalized LI with an 8-day delay between pre-exposure and conditioning. This experiment provides further evidence for the robustness of the forgetting of stimulus attributes, and demonstrates that this specific type of forgetting also occurs prior to the learning of a CTA task.     

Augmentation of latent inhibition by electrical stimulation of hippocampus

The effects of low-level hippocampal stimulation on the development of latent inhibition were investigated employing classical conditioning of the nictitating membrane response of rabbits. Four groups were given either (a) no preexposure of the to-be-CS, (b) preexposure, (c) preexposure overlapped by hippocampal stimulation or (d) preexposure overlapped by cortical stimulation, followed by 300 conditioning trials for each group. After conditioning, the hippocampal group was divided into two groups designated HS-1 and HS-2 by means of a post-hoc test for stimulation effects. Conditioning was found to be retarded in all three preexposured groups, with significantly greater retardation (augmentation of latent inhibition) in Group HS-2. The results support a general conception that the hippocampal stimulation produced its effects through the modulation of sensory input.     

Attenuation of latent inhibition by electrical stimulation of hippocampus

The effects of hippocampal stimulation on the development and expression of latent inhibition were investigated employing classical conditioning of the nictitating membrane response of rabbits. Hippocampal stimulation overlapping conditioned stimulus preexposure produced attenuation of latent inhibition, as did stimulation presented during conditioning after preexposure. However, hippocampal stimulation during conditioning in the absence of preexposure had little effect. The results support the hypotheses that in classical conditioning a major function of the hippocampus is the modulation of sensory input, especially input involved in the learned irrelevance of stimuli.     

Dissociating entorhinal and hippocampal involvement in latent inhibition

This study used anatomical cues to suggest a functional dissociation between the roles of the entorhinal cortex and the hippocampus in learning. The authors proposed that the highly convergent inputs to the entorhinal cortex indicate this region may be particularly important for selecting or compressing information. This hypothesis was tested in rabbits (Oryctolagus cunniculus) trained on an associative learning task that is a common index of stimulus selection. In this task, known as latent inhibition, preexposure to a stimulus (such as a tone) leads to slowed learning when the same tone is subsequently paired with an outcome (such as an airpuff to the eye). As hypothesized, rabbits with neurotoxic lesions of the entorhinal cortex failed to show slowed learning following preexposure (no latent inhibition) and learned the association faster than control rabbits. In contrast, hippocampal-lesioned animals showed normal (slowed) learning.     

Ventral subiculum involvement in latent inhibition context specificity

The subiculum is the main structure linking the hippocampus with several cortical and subcortical areas. In particular, ventral subiculum might act as an interface between the hippocampus, a contextual information processor, and cortical and subcortical processing systems related to motivation, such as the ventral striatum. Electrophysiological studies have shown a relationship between ventral subiculum and ventral striatum, namely a strong influence on mesolimbic system and the activity of dopaminergic neurons in the ventral tegmental area. Dopamine activity in this system has received special attention for its role in the latent inhibition phenomenon. However, the functional relationship between mesolimbic system and this behavioral process remains unclear. Two experiments were performed to analyze the role of ventral subiculum on latent inhibition. The results showed that ventral subiculum is involved in contextual processing that modulates the expression of latent inhibition. These findings are consistent with electrophysiological studies revealing the ventral subiculum as a structure modulating the mesolimbic DA system and DA release in the nucleus accumbens.     

Context-dependent force coding in motor and premotor cortical areas

In three monkeys trained to finely grade grip force in a visuomotor step-tracking task, the effect of the context on neuronal force correlates was quantitatively assessed. Three trial types, which differed in force range, number, and direction of the force steps, were presented pseudo-randomly and cued with the color of the cursor serving as feedback of the exerted force. Quantitative analyses were made on 85 neurons with similar discharge patterns in the three trial types and significant linear positive (54 cells) or negative (31 cells) correlation coefficients between firing rate and force. An analysis of covariance (ANCOVA) showed that the population slopes for 2-step were steeper than for 3-step trials. Another ANCOVA at the population level, computed on the differences in firing rate and force between force steps, persistently disclosed a significant effect of trial type. For the first two force steps, the differences in firing rate were significantly larger in the 2-step than in the 3-step increase trials. Further analyses revealed that neither the force range nor the number of steps was a unique factor. A small group of neurons was tested in an additional trial series with a uniform cue for all three trials, leading to either a loss of context-dependency or to unexpected changes in firing rate. This demonstrates that the cue color was an important instruction for task performance and neuronal activity. The most important findings are that the context-dependent changes were occurring ”on-line”, and that neurons displaying context-dependency were found in all three lateral premotor cortex hand regions and in the primary motor cortex. Finger muscle activity did not show any context dependency. The context-dependent effect leads to a normalization of the cortical activity. The advantage of normalization is discussed and mechanisms for the gain regulation are proposed. Received: 10 November 1998 / Accepted: 13 March 1999     

Learning and latent inhibition in old mice.

The inhibitory component of selective attention has been compared in young (7-8 weeks) and older (9-10 months) female mice using the latent inhibition (LI) paradigm. LI consists of retardation in conditioning to a stimulus as a consequence of its prior non-reinforced pre-exposure. In the present work, active avoidance of an electric footshock signaled with a sound was used. Avoidances of the electric footshocks were significantly reduced in old relative to young mice which did not differ regarding pain threshold. This likely results from a slower learning in old mice. LI was significantly present and of the same importance in both young (46%) and old (49%) mice. These results suggest that in 8-9 months-old mice, the learning ability is reduced but the inhibitory component of selective attention is not altered.     

Novel factors contributing to the expression of latent inhibition

Behavioral and neural correlates of latent inhibition (LI) during eyeblink conditioning were studied in 2 experiments. In Experiment 1, rabbits (Oryctolagus cuniculus) were conditioned after 8 days of tone conditioned stimulus (CS) presentations or 8 days of context-alone experience. LI was seen in the CS-preexposed rabbits when a relatively intense (5 psi) airpuff unconditioned stimulus was paired with the CS. In Experiment 2, rabbits were given 0, 4, or 8 days of CS preexposures or context-alone experience. Hippocampal activity was monitored from the 8-day CS- or context-exposure rabbits. The LI effect was seen only in rabbits given 4 days of CS preexposure, thus suggesting that LI depended largely on the rate of acquisition in the context-preexposed control group. The neural recordings showed that the hippocampus was sensitive to the relative novelty of the stimuli and the overall context, regardless of whether exposure to stimuli and context promoted LI.     

A neuroleptic-like effect of ceronapril on latent inhibition.

Three experiments that used a latent inhibition procedure to investigate the effects of ceronapril on attentional processes in the rat are reported. Latent inhibition is a behavioural paradigm in which prior exposure to a stimulus with no significant consequences retards subsequent conditioning to that stimulus when it is paired with reinforcement. Latent inhibition reflects a process of learning to ignore, or tune out, irrelevant stimuli, and has been suggested as an animal model of the attentional processes disrupted in the acute phase of schizophrenia. In animals, latent inhibition is disrupted by the administration of low doses of amphetamine and enhanced by the administration of neuroleptics. Ceronapril is an angiotensin converting enzyme inhibitor that has been shown to retard the breakdown of central cholecystokinin. It has been proposed that elevation of cholecystokinin levels in the brain may possess neuroleptic-like properties. We assessed this possibility by determining the effects of ceronapril on latent inhibition using a conditioned emotional response procedure, consisting of three stages: pre-exposure, in which the to-be-conditioned stimulus, a tone, was repeatedly presented without reinforcement; conditioning, in which the pre-exposed stimulus was paired with shock; and test, where latent inhibition was indexed by animals' suppression of licking during tone presentation. In Experiment 1, 20 tone pre-exposures were given, and conditioning consisted of five tone-shock pairings; we assessed the effects of 0.005 mg/kg, 0.05 mg/kg and 0.5 mg/kg ceronapril, compared with vehicle injections. In Experiment 2, five tone pre-exposures were given, and conditioning consisted of two tone-shock pairings: we assessed the effects of 0.05 mg/kg ceronapril, compared with vehicle injections.(ABSTRACT TRUNCATED AT 250 WORDS)     

The chakragati mouse shows deficits in prepulse inhibition of acoustic startle and latent inhibition

The chakragati (ckr) mouse, which was serendipitously created as a result of a transgenic insertional mutation, has been proposed as a model of aspects of schizophrenia. The mice exhibit circling, hyperactivity, reduced social interactions, and enlarged lateral ventricles, which parallel aspects of the pathophysiology of schizophrenia. Deficits in sensorimotor gating and processing of the relevance of stimuli are core features of schizophrenia, which underlie many of the symptoms presented. Measures of prepulse inhibition (PPI) and latent inhibition (LI) can assess sensorimotor gating and processing of relevance in both humans and animal models. We investigated PPI of acoustic startle and LI of aversive conditioning in wild-type, heterozygous, and ckr mice. The ckr mice, which are homozygous for the transgene insertion, but not heterozygous littermates, showed impaired PPI in the absence of any difference in acoustic startle amplitude and showed deficits in LI of conditioning of a light stimulus to footshock, measured as suppression of licking for water in water-restricted mice. Together with the previous evidence for hyperactivity, reduced social interactions, and enlarged lateral ventricles, these data lend further support to the suggestion that the ckr mouse has utility as an animal model of aspects of schizophrenia.     

Age reduces cortical reciprocal inhibition in humans

Age alters the control of voluntary movement. A widely observed age-related adaptation is the heightened activation of the antagonist muscles during voluntary movements. We examined the possibility that age also modifies cortical reciprocal inhibition. In young (age 27, n=6) and old (age 73, n=6) adults a mild conditioning electrical stimulus was delivered to the median nerve at the elbow. The test stimulus, delivered by transcranial magnetic stimulation (TMS) at 1-ms increments between 11 and 24 ms after the electrical conditioning stimulus, evoked motor potentials (MEP) in the extensor carpi radialis (ECR) and flexor carpi radialis (FCR). The absolute TMS intensity, expressed as the percent of stimulator output, used to produce 1-mV control MEPs in the ECR was similar in young (mean 58.5, standard deviation ±12.8%) and old adults (60.3±20.3%, P=0.855). The size of the control MEP in the ECR was also similar in young (0.98±0.10 mV) and old subjects (0.90±0.14 mV, P=0.686). The age by conditioning interval interaction (P=0.001) showed that the MEPs in the ECR were significantly depressed at 14, 15, 16, 17, 18, and 19 ms (range 55.5--65.9% of control, all P<0.05) compared with control value of 100% and with old adults who showed no depression. The MEPs remained at control level in the FCR and were also unaffected in the first dorsal interosseus. These data confirm the existence of cortical reciprocal inhibition reported previously in young humans and show that age reduces this inhibition similarly to the previously reported reduction of spinal reciprocal inhibition reported in old adults. Activation of agonist and antagonist muscle pairs are most likely organized around a dual system of cortically and spinally mediated reciprocal inhibition that is altered by age. The data also indicate the need to use age-matched control subjects when comparing individuals with abnormalities resulting from disorders that occur at an old age.     

Rolipram attenuates MK-801-induced deficits in latent inhibition

Latent inhibition is used to examine attention and study cognitive deficits associated with schizophrenia. Research using MK-801, an N-methyl-D-aspartate (NMDA) open channel blocker, implicates glutamate receptors in acquisition of latent inhibition of cued fear conditioning. Evidence suggests an important relationship between NMDA-induced increases in cyclic adenosine monophosphate (cAMP) and learning and memory. The authors examine whether amplification of the cAMP signaling pathway by rolipram, a selective Type 4 cAMP phosphodiesterase inhibitor, reverses MK-801-induced impairments in latent inhibition. One day before training, mice were injected with MK-801, rolipram, MK-801 and rolipram, or vehicle and received 20 preexposures or no preexposures to an auditory conditioned stimulus (CS). Training consisted of 2 CS-footshock unconditioned stimulus pairings. Rolipram attenuated the disruptive effect of MK-801 on latent inhibition, which suggests a role for the cAMP signaling pathway in the task and implicates phosphodiesterase inhibition as a target for treating cognitive impairments associated with schizophrenia.     

Effect of volitional inhibition on cortical inhibitory mechanisms

To investigate the effect of volitional inhibition on cortical inhibitory mechanisms, we performed transcranial magnetic stimulation (TMS) studies with a Go/NoGo reaction task in seven healthy subjects. Subjects were asked to extend their right index finger only after Go, but to remain relaxed after NoGo. Single- and paired-pulse TMS were triggered at the average reaction time for the Go response in each subject after Go or NoGo cues. Motor evoked potentials were recorded in the extensor indicis proprius (EIP) and abductor digiti minimi (ADM) muscles of right hand. Paired-pulse TMS with subthreshold conditioning stimuli at interstimulus intervals (ISIs) of 2 ms [short intracortical inhibition (SICI)] and 15 ms [intracortical facilitation (ICF)] and that with suprathreshold conditioning stimuli at ISI of 80 ms [long intracortical inhibition (LICI)] were performed in both Go/NoGo and control conditions. Inhibition of SICI was enhanced in both EIP and ADM after NoGo and was reduced only in EIP after Go. Inhibition of LICI was reduced in both muscles during both conditions, while ICF was not altered. The present results demonstrate that volitional inhibition enhances SICI but reduces LICI nonselectively. These results suggest that these two inhibitory mechanisms act differently during execution and suppression of voluntary movements.