Serotonin, the superior colliculus, and grooming behavior in cats with neocortical lesions.

Previous studies of cats with pontile lesions indicate that a serotonergic deficit exists in the superior colliculi and that this deficit is involved in the genesis of an abnormal grooming behavior. Cats with frontal neocortical lesions exhibit the same serotonergic deficit and the same abnormal grooming behavior. The present study established that the serotonergic deficit is involved in the mediation of the abnormal grooming behavior in cats with frontal neocortical lesions. Microinjections of 5-hydroxytryptophan (5-HTP) and 5-hydroxytryptamine (5-HT) into the superior colliculi abolished or signigicantly reduced the abnormal behavior in cats with frontal neocortical lesions, whereas no effects of 5-HTP were observed after injections into the cerebrospinal fluid above the superior colliculi, into the tegmentum beneath the superior colliculi, or into the medial dorsal nucleus rostral to the superior colliculi. Other substances (tryptophan, noradrenaline, and gamma-amino-butyric acid) had no effect on the abnormal behavior when injected into the superior colliculi. Further evidence implicating a serotonergic deficit in the mediation of the abnormal behavior was obtained by systemic injections: The abnormal behavior was abolished with 5-HTP in cats with frontal neocortical lesions and in adrenalectomized cats that were previously treated with p-chlorophenylalanine.. The present study also demonstrated that the abnormal grooming behavior is induced by frontal neocortical lesions and not by more caudal lesions of the neocortex. The anatomical relations between the frontal neocortex and the superior colliculus and the role of these structures in grooming behavior are discussed.     

Role of glucocorticoids in an abnormal grooming behavior in cats with pontile or frontal neocortical lesions.

Cats with pontile or frontal neocortical lesions display a tactually elicited dissociation of appetitive and consummatory grooming behaviors. Systemic administration of glucocorticoids abolished the abnormal grooming behavior in cats with lesions, even when the stimulatory effect of glucocorticoids on serotonin metabolism was blocked by administration of p-chlorophenylalanine (PCPA). Microinjections of glucocorticoids into the superior colliculi also significantly decreased the abnormal grooming behavior. Adrenalectomized cats did not display the abnormal grooming behavior, but the abnormal behavior did occur in PCPA-treated adrenalectomized cats. Administration of either glucorticoids or 5-hydroxytryptophan abolished the abnormal behavior in PCPA-treated adrenalectomized cats. Thus, it appears that the pontile and frontal neocortical lesions produce deficits in both glucocorticoids and serotonin, and these deficits are necessary and sufficient conditions for inducing the abnormal grooming behavior.     

Similarities in the physiological bases of an abnormal grooming behavior in thyroidectomized cats and in cats with lesions of the central nervous system.

Thyroidectomized cats display a dissociation of the appetitive and consummatory components of grooming behavior when the body surface is tactually stimulated, an abnormal behavior that also occurs in cats with pontile or frontal neocortical lesions. Systemic administration of 5-hydroxytryptophan (5-HTP) abolishes the abnormal behavior, whereas dihydroxyphenylalanine administration does not, and p-chlorophenylalanine (PCPA) administration induces the abnormal grooming behavior in thyroidectomized cats that are not displaying the abnormal behavior because of spontaneous seasonal reversions. Microinjections of 5-HTP or serotonin into the superior colliculi also abolish the abnormal grooming behavior in thyroidectomized cats. Lesions of the superior colliculi prevent the development of the abnormal behavior after thyroidectomy, even with PCPA treatment. These pharmacological results in thyroidectomized cats parallel the behavioral effects observed in cats with pontile or frontal neocortical lesions.     

Visual sampling after lesions of the superior colliculus in rats

In two separate experiments, rats with bilateral lesions of the superior colliculus showed significantly poorer relearning of a horizontal/vertical stripe discrimination than control animals. In Experiment 1, all animals showed disruption of performance when a stimulus--response (S--R) separation was introduced by raising the stimuli above the site of responding. However, the colliculectomized rats were much more disturbed by the S--R separation than were animals in the control group. In Experiment 2, all animals showed lower performance levels when conflicting patterns were introduced into the upper portion of the stimulus doors, but this time the rats with collicular lesions were less disturbed than the control animals. It is suggested (a) that when the stimulus and response sites are discontiguous, animals must make an appropriate orienting response in order to effectively sample the visual stimuli and (b) that lesions of the superior colliculus alter performance by interfering with this orienting behavior. The impairment in relearning is tentatively attributed to the absence of preoperative overtraining on the discrimination task.     

Visual discrimination learning in rats with lesions of superior colliculus: Door-push and approach errors in modified jumping stand

It has been suggested that, for some species, lesions of the superior colliculus affect visual discrimination learning, but only in certain conditions: (a) when problems are first learnt only after operation, or (b) when discriminanda require detailed scanning, or (c) when “approach” responses to the discriminanda are measured, rather than the response of actually touching them. These suggestions were examined in rats learning visual discriminations in a modified jumping-stand apparatus, after sustaining large lesions of the superior colliculus (and in some cases also of the pretectum). The lesions produced open-field hyperactivity and reduced exploration, indicating effective tectal damage, but the rats learnt a series of difficult discriminations in a door-push task as fast as normal rats, and they did not make more approach errors. Their main abnormality in the discrimination apparatus was that they looked less often between the stimulus doors before stepping across to one of them from the central platform. It is suggested that in rats, as in other animals, lesions of the superior colliculus disrupt the control of scanning head and eye movements; in rats, however, such disruption need not affect discrimination learning (at least in some kinds of apparatus), possibly because the retina of the rat has a relatively poorly developed area centralis.     

Contrasting effects of lateral striate and superior colliculus lesions on visual discrimination performance in rhesus monkeys.

Rhesus monkeys with lesions of lateral striate cortex, monkeys with superior colliculus lesions, and unoperated monkeys were tested for retention of a preoperatively acquired pattern discrimination. The three groups of monkeys were then tested in two-choice, color, color discrimination tests, one involving varying degrees of stimulus-response (S-R) separation and the other, administered several months later, involving various directions of S-R separations. The monkeys were also tested in a series of two-choice pattern discriminations, following each of which they were tested for relearning when the patterns were masked with bars or circles. The monkeys with lateral striate lesions were moderately retarded in retention of the pattern discrimination, whereas those with superior colliculus lesions were not. The monkeys with colliculus lesions, but not those with lateral striate lesions, were impaired in both S-R separation tests, which demonstrates that their deficit was not transient or solely due to a difficulty in shifting the gaze in one direction. The lateral striate monkeys, unlike those with colliculus lesions, were dificient in relearning discriminations between masked patterns. These findings suggest that superior colliculus and striate cortex may be involved in two different aspects of attention: respectively, shifting attention (and orientation) from one spatial locus to another and maintaining attention on fixated stimuli. Alternative interpretations of the effects of the lesions, based on their retinotopic loci, are discussed.     

Orientation to visual stimuli and the superior colliculus in the rat

Rats were trained in a six-choice jumping stand apparatus to enter the dark door, and avoid the five bright doors. Rats with bilateral superior collicular lesions were found to be severely impaired in this task, although further experiments showed that they were able to discriminate bright from dark stimuli and could perform correctly if allowed to approach each door in turn. It is suggested that the superior colliculus is important in orientation to visual cues, and there is some evidence that it is involved in orientation to brightness but not visual form cues.     

Sensorimotor responsiveness in rats with unilateral superior collicular and amygdaloid lesions.

Large unilateral lesions of superior colliculus, but not amygdala, result in strong ipsiversive progression tendencies and permanent neglects of visual, auditory, and whisker-touch stimuli presented on the contralateral side of the body. Combined collicular-amygdaloid lesions also yield circling behaviors and multimodal neglects that are completely independent of the order or laterality of the amygdaloid lesion. Rats with colliculectomy either neglect or else turn away from pinches of the contralateral ear and forepaw. Subjects with combined lesions display more crossed orientations, and this tendency is greatly potentiated by ipsilateral lesion placement. The nature and time course of the crossed response in rats with sensory neglects is reminiscent of the clinical syndrome described as alloaesthesia or as contralateral sensory displacement.     

Time-discrimination performance in cats with lesions in prefrontal cortex and caudate nucleus.

Cats were trained on a time-discrimination task in which different periods of bodily confinement served as discriminanda for go-left/go-right responding. Lesions of gyrus proreus or the associated anteroventral part of nucleus caudatus impaired relearning in this situation. After reacquisition, animals with caudate lesions received proreal ablations and animals with cortical damage received caudate lesions; both additional lesions caused reappearance of the deficit. The absence of external stimuli to signal locus of reinforcement at the moment of spatial choice may have been crucial for eliciting the deficit. The data support the notion that the prefrontal cortex and the anatomically related part of the caudate nucleus participate in similar behaviors.     

Stimulation of the lateral geniculate,superior colliculus,or visual cortex is sufficient for eyeblink conditioning in rats

The role of the cerebellum in eyeblink conditioning is well established. Less work has been done to identify the necessary conditioned stimulus (CS) pathways that project sensory information to the cerebellum. A possible visual CS pathway has been hypothesized that consists of parallel inputs to the pontine nuclei from the lateral geniculate nucleus (LGN), superior colliculus (SC), pretectal nuclei, and visual cortex (VCTX) as reported by Koutalidis and colleagues in an earlier paper. The following experiments examined whether electrical stimulation of neural structures in the putative visual CS pathway can serve as a sufficient CS for eyeblink conditioning in rats. Unilateral stimulation of the ventral LGN (Experiment 1), SC (Experiment 2), or VCTX (Experiment 3) was used as a CS paired with a periorbital shock unconditioned stimulus. Stimulation was delivered to the hemisphere contralateral to the conditioned eye. Rats in all experiments were given five 100-trial sessions of paired or unpaired eyeblink conditioning with the stimulation CS followed by three paired sessions with a light CS. Stimulation of each visual area when paired with the unconditioned stimulus supported acquisition of eyeblink conditioned responses (CRs) and substantial savings when switched to a light CS. The results provide evidence for a unilateral parallel visual CS pathway for eyeblink conditioning that includes the LGN, SC, and VCTX inputs to the pontine nuclei.Pavlovian eyeblink (eyelid closure and nictitating membrane movement) conditioning is established by pairing a conditioned stimulus (CS), usually a tone or light, with an unconditioned stimulus (US) that elicits the eyeblink reflex. The eyeblink conditioned response (CR) emerges over the course of paired training, occurs during the CS, and precedes the US (Gormezano et al. 1962; Schneiderman et al. 1962). Neurobiological investigations of Pavlovian eyeblink conditioning have primarily focused on the cerebellum, which is the site of memory formation and storage (Thompson 2005). The anterior interpositus nucleus is necessary for acquisition and retention of the eyeblink CR (Lavond et al. 1985; Krupa and Thompson 1997; Freeman Jr. et al. 2005; Thompson 2005; Ohyama et al. 2006). Lobule HVI and the anterior lobe of the cerebellar cortex (lobules I–V) contribute to acquisition, retention, and timing of the CR (McCormick and Thompson 1984; Perrett et al. 1993; Perrett and Mauk 1995; Attwell et al. 1999, 2001; Medina et al. 2000; Nolan and Freeman Jr. 2005; Nolan and Freeman 2006). The brainstem nuclei that comprise the proximal ends of the CS and US input pathways to the cerebellum have also been identified.The pontine nuclei (PN) and inferior olive (IO) receive CS and US information, respectively, and are the primary sensory relays into the interpositus nucleus and cerebellar cortex (Thompson 2005). Conditioned stimulus information converges in the PN, which receives projections from lower brainstem, thalamus, and cerebral cortex (Glickstein et al. 1980; Brodal 1981; Schmahmann and Pandya 1989; Knowlton et al. 1993; Campolattaro et al. 2007). The lateral pontine nuclei (LPN) are the sources of auditory CS information projected into the cerebellum. Lesions of the LPN block CR retention to a tone CS, but have no effect on CRs to a light CS (Steinmetz et al. 1987). Thus, CS inputs from different sensory modalities may be segregated at the level of the PN. Neurons in the PN project CS information into the contralateral cerebellum via mossy fibers in the middle cerebellar peduncle that synapse primarily on granule cells in the cerebellar cortex and on neurons in the deep nuclei (Bloedel and Courville 1981; Brodal 1981; Steinmetz and Sengelaub 1992). Stimulation of the PN acts as a supernormal CS supporting faster CR acquisition than conditioning with peripheral stimuli (Steinmetz et al. 1986, 1989; Rosen et al. 1989; Steinmetz 1990; Tracy et al. 1998; Freeman Jr. and Rabinak 2004). The primary focus of these experiments was to investigate the most proximal components of the CS pathway in eyeblink conditioning. There has been less emphasis on identifying the critical CS pathways that project information to the PN.Recent studies using lesions, inactivation, stimulation, and neural tract tracing have provided evidence that the auditory CS pathway that is necessary for acquisition and retention of eyeblink conditioning is comprised of converging inputs to the medial auditory thalamic nuclei (MATN), and a direct ipsilateral projection from the MATN to the PN (Halverson and Freeman 2006; Campolattaro et al. 2007; Freeman et al. 2007; Halverson et al. 2008). Unilateral lesions of the MATN, contralateral to the conditioned eye, block acquisition of eyeblink CRs to a tone CS but have no effect on conditioning with a light CS (Halverson and Freeman 2006). Inactivation of the MATN with muscimol blocks acquisition and retention of CRs to an auditory CS, and decreases metabolic activity in the PN (Halverson et al. 2008). The MATN has a direct projection to the PN and stimulation of the MATN supports rapid CR acquisition (Campolattaro et al. 2007). Our current model of the auditory CS pathway consists of converging inputs to the MATN, and direct unilateral thalamic input to the PN (Halverson et al. 2008).Less work has been done to identify the visual CS pathway necessary for eyeblink conditioning. A possible parallel visual CS pathway has been hypothesized, which includes parallel inputs to different areas of the PN from the lateral geniculate nucleus (LGN), superior colliculus (SC), visual cortex (VCTX), and pretectal nuclei (Koutalidis et al. 1988). In the Koutalidis et al. study, lesions of the LGN, SC, VCTX, or pretectal nuclei alone had only a partial effect on CR acquisition with a light CS. Lesions of any two of these structures together produced a more severe impairment on acquisition and combined lesions of all of these areas completely blocked CR acquisition to a light CS (Koutalidis et al. 1988). Each visual area investigated in the Koutalidis et al. study has a direct projection to the PN that could be important for eyeblink conditioning. The ventral LGN projects to the medial, and to a lesser extent, the lateral PN (Graybiel 1974; Wells et al. 1989). The superficial, intermediate, and deep layers of SC send projections to both the dorsomedial and dorsolateral PN (Redgrave et al. 1987; Wells et al. 1989). The VCTX has a direct projection to the rostral and lateral portions of the PN (Glickstein et al. 1972; Baker et al. 1976; Mower et al. 1980; Wells et al. 1989). The pretectal nuclei also have a direct projection to both the medial and lateral PN (Weber and Harting 1980; Wells et al. 1989). However, stimulation of the anterior pretectal nucleus is not an effective CS for eyeblink conditioning (Campolattaro et al. 2007). The failure to establish conditioning with stimulation of the anterior pretectal nucleus as a CS suggests that there may be differences in the efficacy of the various visual inputs to the PN for cerebellar learning. The following experiments investigated the sufficiency of stimulation of the LGN, SC, or primary VCTX as a CS for eyeblink conditioning in rats.