Decreased striatal c-Fos accompanies latent inhibition in a conditioned taste aversion paradigm

Latent inhibition (LI) is a phenomenon whereby previous exposure to a stimulus retards subsequent acquisition of a conditioned response to that stimulus. The present study investigated the neuronal substrates of LI as assessed in a conditioned taste aversion paradigm by comparing regional c-Fos activation in pre- vs. non-pre-exposed animals. The LI paradigm involved a pre-exposure phase in which water-deprived rats were allowed access to either water (non-pre-exposed; NPE) or 5% sucrose (pre-exposed; PE), followed by a conditioning phase in which animals were allowed access to sucrose and subsequently injected with lithium chloride, and a test phase in which animals were allowed access to both sucrose and water. LI was assessed by comparing the %-sucrose consumed in PE and NPE groups on the test day. Two hours following the onset of the test phase, animals were perfused and their brains processed for c-Fos immunohistochemistry. PE animals drank significantly more sucrose on the test day, indicating the presence of LI. PE animals had significantly fewer FLI-positive cells in the striatum than NPE animals; however, no differences were seen in the nucleus accumbens. This difference in FLI was not due to a difference in sucrose consumption on the test day as there was no correlation between c-Fos and amount of sucrose consumed in the PE group. These data are consistent with previous data supporting a role for the striatum in the disruption of LI as assessed by CTA.     

Role of gender in the behavioral effects of peripheral sympathetic ingrowth

Following cholinergic denervation of the hippocampal formation, peripheral sympathetic nerves originating from the superior cervical ganglia grow into the hippocampus. As gender is known to alter the anatomy of hippocampal sympathetic ingrowth, we assessed the effect of this variable on the behavioral recovery following ingrowth. Adult male or female rats were trained on a standard version of a radial-8-arm maze task until they reached a specific learning criterion. Animals from each sex then underwent one of three surgical procedures: sham surgery, medial septal lesions plus superior cervical ganglionectomy, or medial septal lesion plus sham ganglionectomy. Reacquisition of the maze was then assessed. Prior to surgery, male animals acquired the task significantly faster than female animals. Following surgery male and female rats recovered overall performance at similar rates. However, marked group differences were observed. In males, the control group recovered faster than the group with medial septal lesion plus ganglionectomy, which recovered faster than the medial septal lesion group. In females, the control group recovered faster than the medial septal lesion group, which in turn recovered faster than the medial septal ganglionectomy group. The results of this study clearly demonstrate that gender can influence the behavioral effects of hippocampal sympathetic ingrowth. We believe that this is the first report in which gender has been shown to alter the behavioral effect of a neuronal reorganization.     

Visual search in schizophrenia: latent inhibition and novel pop-out effects

A visual search task was used to assess attentional function in a mixed group of schizophrenic patients and in normal controls. Subjects identified presence or absence of a unique shape presented with homogeneous distractors. Response time (RT) was examined as a function of prior experience with target, distractor, or both. On each trial, targets and/or distractors were either novel or familiar. Schizophrenic patients were slower than controls in all conditions. In the test phase, three target/distractor conditions were examined (PE - target and distractors pre-exposed but reversed; NPE - target novel and distractors pre-exposed; NOV - novel target and distractors). As predicted, normal controls, but not schizophrenics, showed latent inhibition (LI: PE minus NPE). The latter finding was due to the absence of normal LI in female patients. A novel pop-out effect (NOV minus NPE) was obtained which did not interact with any of the other variables. The results suggest that the LI effect is indeed related to the processing of irrelevant stimuli, and that, at least female schizophrenic patients process such stimuli differently from controls. Past inconsistencies in the LI-schizophrenia literature may be the result of disproportionate gender compositions in patient and control groups.     

Intact visual latent inhibition in schizophrenia patients in a within-subject paradigm

People are normally slower to learn a CS-UCS association if they first experience the CS without the UCS. This normal slowing, termed "latent inhibition" (LI), is reported by some to be absent in schizophrenia patients. Our previous studies detected generalized learning deficits but not LI deficits in schizophrenia patients, using between-subject auditory and visual LI paradigms. To understand our divergent results, we developed a within-subject visual LI paradigm that detects LI in normal male subjects that we previously reported to be disrupted by acute treatment with dopamine agonists. In the present study, we verified the ability of this dopamine-sensitive within-subject LI paradigm to detect LI among both male and female normal control subjects, and then used this paradigm to assess LI in schizophrenia patients. Among normals, LI exhibited no sex differences or menstrual cyclicity. Compared to normals, schizophrenia patients exhibited learning deficits with both preexposed (PE) and non-preexposed (NPE) stimuli. Despite these generalized deficits, both acutely hospitalized patients and stable outpatients with schizophrenia exhibited robust LI, as evidenced by significantly faster learning with NPE than PE stimuli. LI deficits in schizophrenia may be paradigm-specific and are not detected by a paradigm that we previously reported to be sensitive to disruption by dopamine agonists.     

Lesions of the dopaminergic innervation of the nucleus accumbens medial shell delay the generation of preference for sucrose, but not of sexual pheromones

Male sexual pheromones are rewarding stimuli for female mice, able to induce conditioned place preference. To test whether processing these natural reinforcing stimuli depends on the dopaminergic innervation of the nucleus accumbens, as for other natural rewards, we compare the effects of specific lesions of the dopaminergic innervation of the medial shell of the nucleus accumbens on two different appetitive behaviours, ‘pheromone seeking’ and sucrose preferential intake. Female mice, with no previous experience with either adult male chemical stimuli or with sucrose, received injections of 6-hydroxydopamine (or vehicle) in the medial shell of the accumbens. Then, we analyzed their preference for male soiled-bedding and their preferential intake of a sucrose solution, with particular emphasis on the dynamics of acquisition of both natural rewards.The results indicate that both lesioned and sham animals showed similar preference for male sexual pheromones, which was constant along the test (linear dynamics). In contrast, lesioned animals differed from sham operated mice in the dynamics of sucrose consumption in their first test of sucrose preference. Sham animals showed an initial sucrose preference followed by preference for water, which can be interpreted as sucrose neophobia. Lesioned animals showed no preference at the beginning of the test, and a delayed sucrose preference appeared followed by a delayed neophobia. The next day, during a second sucrose-preference test, both groups displayed comparable and sustained preferential sucrose intake. Therefore, dopamine in the medial shell of the nucleus accumbens has a different role on the reward of sexual pheromones and sucrose.     

Sympathetic sprouting and recovery of a spatial behavior

After lesions of the medial septum, peripheral sympathetic fibers from the superior cervical ganglion appear in the hippocampal formation. To assess the functional significance of this neuronal rearrangement, we analyzed behavior on a spatial/memory task sensitive to hippocampal dysfunction, the radial eight-arm maze. The procedure allowed evaluation of both working and reference memory. All rats were able to master the task. Half of the rats then underwent either medial septal lesions and ganglionectomy or sham neurosurgery and ganglionectomy, and the other half underwent medial septal lesions or sham neurosurgery followed by ganglionectomy after further behavioral testing. Medial septal lesions in both groups disrupted taks performance with recovery of performance occurring with time. However, the rate of recovery was significantly enhanced in rats which had septal lesions and ganglionectomies simultaneously. Removal of the ganglion after recovery produced no effects on maze performance. Our results suggest that sympathetic ingrowth retards recovery processes.     

Behavioural and cardiovascular responses during latent inhibition of conditioned fear: measurement by telemetry and conditioned freezing

This study assessed freezing behaviour and cardiovascular responses during the expression of latent inhibition of conditioned fear. Animals that were either repeatedly preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (non-preexposed; NPE) subsequently experienced three presentations of the tone paired with footshock. Animals were tested 24 h later in the context of the footshock chamber, and on the following day, in the presence of the tone CS. Changes in heart rate and blood pressure were recorded by radio-telemetry. The PE rats spent more time freezing to the conditioned contextual cues and exhibited higher blood pressures during the last half of the context test session than did the NPE animals. During the tone test, the PE rats exhibited less conditioned freezing to the tone CS compared with the NPE animals, i.e. expression of the latent inhibition. This behavioural effect was associated with a significant increase in heart rate, but not blood pressure, in the PE but not the NPE animals. Our results suggest that the increased blood pressures of the PE rats during the context test directly reflect their greater fear of the conditioning context. In contrast, the increased heart rate response but decreased freezing shown by PE rats in response to the tone CS may be due to the fact that lower stress levels (e.g. PE condition) elicit sympathetically-mediated increases in heart rate, whereas higher stress levels (e.g. NPE condition) activate both sympathetic and parasympathetic systems, thus eliminating any CS-induced increase in heart rate in the NPE rats.     

Effects of microinjections of apomorphine and haloperidol into the inferior colliculus on the latent inhibition of the conditioned emotional response

Electrical or chemical stimulation of the inferior colliculus (IC) induces fear-like behaviors. More recently, consistent evidence has shown that electrical stimulation of the central nucleus of the IC supports Pavlovian conditioning and latent inhibition (LI). LI is characterized by retardation in conditioning and also by an impaired ability to ignore irrelevant stimuli, after a non-reinforced pre-exposure to the conditioned stimulus. LI has been proposed as a behavioral model of cognitive abnormalities seen in schizophrenia. The aim of the present study was to determine whether dopaminergic mechanisms in the IC are involved in LI of the conditioned emotional response (CER). To induce LI, a group of rats was pre-exposed (PE) to six tones in two sessions, while rats that were not pre-exposed (NPE) had two sessions without tone presentations. The conditioning consisted of two tone presentations to the animal, followed immediately by a foot shock. PE and NPE rats received IC microinjections of physiological saline, the dopaminergic agonist apomorphine (9.0 μg/0.5 μL/side), or the dopaminergic antagonist haloperidol (0.5 μg/0.5 μL/side) before both pre-exposure and conditioning. During the test, the PE rats that received saline or haloperidol had a lower suppression of the licking response compared to NPE rats that received vehicle or haloperidol, indicating that latent inhibition was induced. There was no significant difference in the suppression ratio in rats that received apomorphine injections into the IC, indicating reduced latent inhibition. These results suggest that dopamine-mediated mechanisms of the IC are involved in the development of LI.     

Effects of metabotropic glutamate receptor 5 on latent inhibition in conditioned taste aversion

Latent inhibition (LI) is a phenomenon by which pre-exposure of a conditioned stimulus (CS) prior to the CS-unconditioned stimulus (US) pairings retards conditioned responding (CR). LI has been demonstrated in a variety of learning tasks including conditioned taste aversion (CTA). Earlier work has shown that systemic administration of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective metabotropic glutamate receptor 5 (mGlu5) antagonist, is able to disrupt classical conditioning in CTA. The present study investigated the involvement of mGlu5 receptors in LI using a CTA procedure. In the first experiment, rats received either water (non-pre-exposed, NPE) or a saccharin solution (pre-exposed, PE) on 2 consecutive days. The animals then received conditioning in which a fixed amount of saccharin was paired with lithium chloride and then the CR to the taste was tested. Either MPEP (3, 6, 12 mg/kg) or vehicle was injected intraperitoneally prior to taste pre-exposure or testing. Animals in the vehicle control groups displayed LI. MPEP injections before pre-exposure trials attenuated LI but also reduced consumption during pre-exposure, which obscured interpretation of the LI effect. The second experiment used four pre-exposure trials and controlled access to fixed amount of the solutions during the pre-exposure as well as the conditioning trials. Rats were injected before pre-exposure trials but not before the test trial. The results found that MPEP attenuates latent inhibition suggesting that the mGlu5 receptor exerts an influence on the processes that underlie the effects of taste pre-exposure on conditioning.     

Interaction of neurotransmitter systems in the hippocampus: a study of some behavioral effects of hippocampal sympathetic ingrowth.

Recent research has suggested that normal learning/memory may depend upon the balance between central noradrenergic and cholinergic systems. This hypothesis has particular relevance to the study of the neuronal rearrangement that follows cholinergic denervation of hippocampus. In this, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus in response to lesions of the medial septal (MS) cholinergic cell bodies. To understand further the influence of hippocampal sympathetic ingrowth (HSI) on behavior, gustatory neophobia, passive avoidance (PA) learning, and open field activity were studied. Male Sprague-Dawley rats underwent one of four surgical procedures: MS lesions and sham ganglionectomy (ingrowth group; MS/HSI group), sham MS lesions and ganglionectomy (Gx group), MS lesions and ganglionectomy (no-ingrowth group; MS/Gx group), or sham MS lesions and sham ganglionectomy (CON group). Behavioral testing began 4 weeks following surgery. The time to acquire the PA task was similar among all groups; however, the initial latency to enter the dark chamber of the PA apparatus was longer, and the number of partial reentries greatest, for MS/HSI animals. Retention testing at 24 hr revealed that MS/HSI animals were significantly impaired when compared to the CON and MS/Gx groups. The MS/Gx and the CON groups demonstrated gustatory neophobia, preferring water to saccharin solution, while gustatory neophobia was absent in the MS/HSI and Gx groups. MS/HSI animals were found to be more active in the open field than the other groups. Biochemical studies revealed the expected loss of ChAT activity in the dorsal and ventral hippocampi of lesioned animals along with elevated levels of norepinephrine (NE) in the dorsal hippocampus of MS/HSI animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Excitotoxic basolateral amygdala lesions potentiate the memory impairment effect of muscimol injected into the medial septal area

In rats, the septo-hippocampal system is important for memory encoding. Previous reports indicate that muscimol, a specific GABAergic agonist induces learning and memory deficits when infused into the medial septal area. The basolateral nucleus of the amygdala (BLA) modulates memory encoding in other brain areas, including the hippocampus. To explore the interactions between the septo-hippocampal system and amygdala in memory, we studied the effects of intra-medial septal infusions of muscimol in rats with BLA lesions. Animals received sham surgery or excitotoxic BLA lesions and were given infusions of either vehicle or muscimol (5 nmol) into the medial septal area 5 min prior to training sessions in inhibitory avoidance and water maze tasks. In the inhibitory avoidance task, muscimol-induced memory impairment was potentiated by BLA amygdala lesions. Additionally, in the water maze task, BLA-lesioned rats given muscimol infusions into the medial septal also showed memory impairment. These findings indicate that the MSA interacts with the BLA in the processing of memory storage.     

A neurotoxic lesion of serotonergic neurones using 5,7-dihydroxytryptamine does not disrupt latent inhibition in paradigms sensitive to low doses of amphetamine

Testing the effects of low doses of d-amphetamine on latent inhibition (LI) in two different conditioning paradigms, passive avoidance and conditioned taste aversion, provided evidence of their pharmacological equivalence. For passive avoidance, LI was expressed by the decreased latency to enter a shock compartment in preexposed rats placed 5 min in the compartment during 3 consecutive days before conditioning. In the conditioned taste aversion paradigm, a group of rats was preexposed to a solution of sucrose also for 3 consecutive days prior to the establishment of an association between sucrose and sickness elicited by an injection of LiCl. On the following day, the preexposed rats drunk more sucrose when allowed to choose between one tube containing water and an other containing sucrose. In both paradigms, 0.25 mg/kg d-amphetamine, injected daily on the 3 preexposure days and on the conditioning day, decreased LI. A dose of 0.5 mg/kg suppressed LI in the passive avoidance paradigm. The effect of a serotonergic lesion induced by i.c.v. injection of 5,7-dihydroxytryptamine (5,7-DHT) was evaluated in the same paradigms. The lesion procedure that lowered hippocampal serotonin and 5 HIAA levels by more than 80% did not affect LI. Taken together, the present results lessens the hypothesis that LI is prone to an opposing influence of the two monoaminergic systems considered in this work.     

The effects of delaying reward on choice preference in rats with hippocampal or selective septal lesions

Two experiments are reported in which rats were trained to choose one of two goal arms in a Y-maze, for water reward. In one arm, the rats always received water (the continuously reinforced-CRF-arm). In the other arm the rats only sometimes received water (the partially reinforced-PRF-arm). During the critical test phase in both experiments, we delayed the reward in the CRF arm only by 10 s. Experiment 1 tested intact rats given saline injections, or injections of chlordiazepoxide hydrochloride (Librium, 5 mg/kg), and rats with hippocampal or cortical control lesions. When reward was immediate in both arms all rats preferred the CRF arm. Once reward was delayed, the rats with hippocampal lesions switched their preference to the PRF arm, while the rats in the other treatment groups did not. Experiment 2 tested rats with medial septal lesions, lateral septal lesions or control operations in the same way. The rats with medial septal lesions, and to a lesser extent those with lateral septal lesions, switched their preference to the PRF arm when compared to the sham-operated controls. We conclude that damage to the hippocampus or its afferent pathway from the septum increases rats' sensitivity to temporal discontiguities between the outcome of a response and its emission.     

Effects of GABAergic drugs, fornicotomy, hippocampectomy and septal lesions on the extinction of a discrete-trial fixed ratio 5 lever-press response

The effects of certain GABA-modulating drugs, fornicotomy, hippocampectomy and various septal lesions were analysed in a discrete-trial fixed ratio 5 (FR5) bar-press paradigm. Chlordiazepoxide, fornicotomy, hippocampectomy, electrolytic lateral septal lesions and ibotenic acid medial septal lesions facilitate extinction of the FR5 response. Some of these treatments (chlordiazepoxide, hippocampectomy, electrolytic lateral septal lesions) have previously been found to increase resistance to extinction of alley-running after continuously reinforced (CRF) acquisition training. The treatments which facilitated extinction in the discrete-trial FR5 paradigm have been found to reduce or abolish the partial reinforcement extinction effect in the alley. These results indicate that the discrete-trial FR5 paradigm is not analogous to a runway CRF schedule, but may be analogous to a runway partial reinforcement schedule.     

Serial position curves for item (spatial location) information: role of the dorsal hippocampal formation and medial septum

Animals were trained on an item recognition memory task for a list of 5 spatial locations. After reaching criterion performance the animals sustained small or medium-size dorsal hippocampal formation lesions, small or large medial septal lesions, or served as sham-operated or cortical controls. Following recovery from surgery, animals were retested for item recognition memory. Sham-operated and cortical control animals showed no deficits in performance. In contrast, animals with small dorsal hippocampal formation or medial septal lesions displayed a deficit for the early items, but had excellent memory for the last item of the list. Animals with medium-size dorsal hippocampal formation or large medial septal lesions displayed a deficit for both early and late items within the list. Because residual short-term memory capacity can be seen only with small hippocampal formation or medial septal lesions, it is suggested that the hippocampal formation and cholinergic input into the hippocampal formation via the medial septum code spatial information within a continuous extended time frame.     

Neonatal functional blockade of the entorhinal cortex results in disruption of accumbal dopaminergic responses observed in latent inhibition paradigm in adult rats

Latent inhibition (LI) has been found to be disrupted in non-treated patients with schizophrenia. Dopaminergic (DAergic) dysfunctioning is generally acknowledged to occur in schizophrenia. Various abnormalities in the entorhinal cortex (ENT) have been described in patients with schizophrenia. Numerous data also suggest that schizophrenia has a neurodevelopmental origin. The present study was designed to test the hypothesis that reversible inactivation of the ENT during neonatal development results in disrupted DA responses characteristic of LI in adult rats. Tetrodotoxin (TTX) was microinjected locally in the left ENT at postnatal day 8 (PND8). DA variations were recorded in the dorsomedial shell and core parts of the nucleus accumbens (Nacc) using in vivo voltammetry in freely-moving grown-up rats in a LI paradigm. In the first session the animals were pre-exposed (PE) to the conditional stimulus (banana odour) alone. In the second they were aversively conditioned to banana odour. In the third (test) session the following results were obtained in PE animals subjected to temporary inactivation of the ENT at PND8: (1) aversive behaviour was observed in TTX-PE conditioned animals; (2) DA variations in the dorsomedial shell and core parts of the Nacc were similar in TTX-PE and non-pre-exposed conditioned rats. These findings strongly suggest that neonatal disconnection of the ENT disrupts LI in adult animals. They may further our understanding of the pathophysiology of schizophrenia.     

Control of sensory activation of granule cells in the fascia dentata by extrinsic afferents: septal and entorhinal inputs

Three groups of rats were trained to perform a differential discrimination task in a 2-tone operant conditioning paradigm. One group received electrolytic lesions of the medial septal nuclei, another received electrolytic or knife cut lesions of the entorhinal cortex. These groups were compared with a normal control group. Recordings of granule cells in the fascia dentata were obtained in all animals during criterion performance of the behavioral task. Both lesions produced disruption of behavioral discrimination in the form of increased error and intertrial responding. Granule cell discharges to the tone stimuli were disrupted by each type of lesion. Septal lesions reduced the differential discharge tendency to CS+ and CS- and changed granule cell firing on all trials to statistically resemble firing on CS- trials in normal animals. Extensive lesions in the entorhinal cortex or knife cuts that severed the perforant path caused near elimination of the tone-evoked discharges to both the CS+ and CS-tones. Septal and entorhinal lesions caused marked changes in the sequential dependence of the granule cell discharge compared with intact animals. Results are discussed in terms of the control of the granule cell discharge by the remaining afferent pathways in each type of lesion condition.     

Functional significance of sympathohippocampal sprouting: changes in single cell spontaneous activity

The electrophysiological consequences of noradrenergic sympathohippocampal ingrowth following medial septal lesions were investigated. Spontaneous activity of single dentate neurons was recorded in anesthetized rats with and without sympathohippocampal ingrowth. In animals with medial septal lesions (ingrowth) spontaneous firing rates were not different from rates in normal animals. Medial septal lesions combined with bilateral superior cervical ganglionectomy (no ingrowth) resulted in a significant 82% increase in spontaneous activity.     

Recovery of function in the albino rat following either simultaneous or seriatim lesions of the caudate nucleus

This study examines acquisition of spatial alteration performance and of passive avoidance behavior following seriatim lesions of the caudate nucleus in mature albino rats. Bilateral destruction of the caudate in one surgical operation has been shown to produce animals with well defined behavioral impairments; thus, the application of the seriatim surgical paradigm provides a means of evaluating the potential of the caudate damaged brain for functional reorganization. Lesions of the caudate nucleus were created by electrocoagulation, either bilaterally at one operation or in two sequential unilateral stages with a 25 day interlesion interval. A sham operated group was also employed. Rats having one-stage caudate lesions were impaired on spatial alternation when compared with two-stage and sham operated animals. Rats with two-stage lesions were better on passive avoidance than subjects with one-stage lesions and sham operated controls. These latter differences could not be accounted for by shock threshold or water consumption differences. There were no differences in the extent of the lesions between the animals that were subjected to one- and two-stage operations. These findings indicate that significant functional differences are produced by one-stage versus two-stage lesions of the rat caudate nucleus.     

Taste aversions conditioned with gamma radiation: Attenuation by area postrema lesions in rats

The role of the area postrema in radiation induced taste aversions in rats was examined. One group of rats received lesions of the area postrema, another group was given sham lesions and a third group received no surgery. These three groups of rats were then given one pairing of 1 h access to a novel 0.15% sodium saccharin solution followed immediately with exposure to 200 rad gamma radiation. A fourth group of rats with area postrema lesions was given 1 h access to saccharin followed by a sham irradiation procedure. Four days later all groups were given daily two bottle preference tests (saccharin vs water) on 5 consecutive days. The groups with sham lesions or no surgery displayed a strong aversion to saccharin on all 5 test days. The two area postrema lesioned groups displayed a moderate and increasing preference for saccharin over the 5 day test period. The lesioned group given radiation treatment showed a weak but significant aversion (P < 0.05) to saccharin on the first test day, when compared to the lesioned rats not given radiation treatment. Thus, lesions of the area postrema strongly attenuated the radiation induced taste aversions, but did not completely abolish them.