Sham-lesioned Control Rats Research Articles

Intermittent Fasting After Spinal Cord Injury Does Not Improve the Recovery of Baroreflex Regulation in the Rat.

Modest recovery of somatic function after incomplete spinal cord injury (SCI) has been widely demonstrated. Recently we have shown that spontaneous recovery of baroreflex regulation of sympathetic activity also occurs in rats. Dietary restriction in the form of every other day fasting (EODF) has been shown to have beneficial effects on the recovery of motor function after SCI in rats. The goal of this study was to determine if EODF augments the improvement of baroreflex regulation of sympathetic activity after chronic left thoracic (T8) surgical spinal hemisection. To determine this, we performed baroreflex tests on ad-lib fed or EODF rats 1 week or 7 weeks after left T8 spinal hemisection. One week after T8 left hemisection baroreflex testing revealed that gain of baroreflex responsiveness, as well as the ability to increase renal sympathetic nerve activity (RSNA) at low arterial pressure, was significantly impaired in the ad-lib fed but not the EODF rats compared with sham lesioned control rats. However, baroreflex tests performed 7 weeks after T8 left hemisection revealed the inability of both ad-lib and EODF rats to decrease RSNA at elevated arterial pressures. While there is evidence to suggest that EODF has beneficial effects on the recovery of motor function in rats, EODF did not significantly improve the recovery of baroreflex regulation of sympathetic activity.

Enhancing second-order conditioning with lesions of the basolateral amygdala.

Because the occurrence of primary reinforcers in natural environments is relatively rare, conditioned reinforcement plays an important role in many accounts of behavior, including pathological behaviors such as the abuse of alcohol or drugs. As a result of pairing with natural or drug reinforcers, initially neutral cues acquire the ability to serve as reinforcers for subsequent learning. Accepting a major role for conditioned reinforcement in everyday learning is complicated by the often-evanescent nature of this phenomenon in the laboratory, especially when primary reinforcers are entirely absent from the test situation. Here, I found that under certain conditions, the impact of conditioned reinforcement could be extended by lesions of the basolateral amygdala (BLA). Rats received first-order Pavlovian conditioning pairings of 1 visual conditioned stimulus (CS) with food prior to receiving excitotoxic or sham lesions of the BLA, and first-order pairings of another visual CS with food after that surgery. Finally, each rat received second-order pairings of a different auditory cue with each visual first-order CS. As in prior studies, relative to sham-lesioned control rats, lesioned rats were impaired in their acquisition of second-order conditioning to the auditory cue paired with the first-order CS that was trained after surgery. However, lesioned rats showed enhanced and prolonged second-order conditioning to the auditory cue paired with the first-order CS that was trained before amygdala damage was made. Implications for an enhanced role for conditioned reinforcement by drug-related cues after drug-induced alterations in neural plasticity are discussed. (PsycINFO Database Record

Enhanced α1 adrenergic sensitivity in sensorimotor gating deficits in neonatal ventral hippocampus-lesioned rats

Neonatal ventral hippocampus (nVH) lesion in rats is a widely used animal model of schizophrenia due to the predominantly post-pubertal emergence of many schizophrenia-like behaviours. Our previous studies have shown increased ligand binding of alpha1 adrenergic receptors (AR) in the frontal cortex of post-pubertal, but not pre-pubertal, nVH-lesioned rats, compared to sham-lesioned control rats. Moreover, pretreatment with the alpha1 adrenergic receptor antagonist prazosin reversed amphetamine-induced hyperlocomotion in controls, but failed to do so in lesioned animals. This led to our hypothesis that nVH lesions may lead to post-pubertal hyperactivity of alpha1 adrenergic receptors. In order to test the functional relevance of alpha1 adrenergic hyperactivity to schizophrenia-like behaviours of nVH-lesioned animals, we conducted prepulse inhibition (PPI) studies in post-pubertal (postnatal days 56-120) sham and lesioned animals in response to systemic injections of alpha1 adrenergic receptor antagonist and agonist, prazosin and cirazoline, respectively. Our results show that PPI deficits in nVH-lesioned animals were reversed with prazosin treatment, without a significant effect on PPI in sham animals. Further, at various doses, cirazoline had a significantly greater PPI disruptive effect in nVH-lesioned animals than in sham animals. Together, these results suggest that nVH-lesioned animals show a hyperactive alpha1 adrenergic receptor system that may mediate sensorimotor gating abnormalities reported in these animals.

Area postrema-lesions increase operant responding to sucrose in rats

Rats with lesions of the area postrema (APX) are known to exhibit an enhanced intake of highly palatable foods such as sweetened condensed milk and cookies. These observations suggest the possibility that APX rats find these foods more rewarding and will work harder to obtain these foods. Sham and APX rats were tested on fixed ratio (FR) and progressive ratio (PR) schedules. APX rats consistently pressed more times to receive sucrose solution and attained both FR 3 and FR 5 criteria significantly faster than sham-lesioned control rats. Furthermore, rats with APX had significantly higher break points than sham-lesioned control rats on a progressive ratio schedule. These results support the hypothesis that rats with lesions of the area postrema will consistently work harder to obtain a highly palatable food reward.

Involvement of the laterodorsal tegmental nucleus in the locomotor response to repeated nicotine administration

The locomotor altering properties of nicotine depend on activation of nicotinic acetylcholine receptors in the ventral tegmental area (VTA). The laterodorsal tegmental nucleus (LDTg) provides a significant proportion of the cholinergic innervation of the VTA. We tested the hypothesis that the locomotor effects of nicotine depend on the functional integrity of the LDTg. The spontaneous locomotor activity of LDTg and sham-lesioned control rats was measured over seven sessions, after which we examined the effects of repeated injections of nicotine in a day on–day off design, giving injections of saline on the nicotine-off days. Spontaneous locomotor activity was significantly lower in LDTg lesioned compared to control rats. LDTg lesions also blunted the effects of nicotine: control rats showed an initial locomotor depression after nicotine, but on repeated testing showed a progressive increase in the amount of locomotion in response to drug challenge. LDTg lesioned rats showed no differences in responding to nicotine compared to saline. These data show that the functional integrity of the LDTg is required in order to show normal locomotor response to nicotine. One explanation for this is that loss of the LDTg affects synaptic activity in the VTA.

Effects of orbital prefrontal cortex dopamine depletion on inter-temporal choice: a quantitative analysis.

Lesions of the orbital prefrontal cortex (OPFC) can cause pathologically impulsive behaviour in humans. Inter-temporal choice behaviour (choice between reinforcers differing in size and delay) has been proposed as a model of "impulsive choice" in animals. We recently found that destruction of the OPFC disrupted inter-temporal choice in rats. It is not known whether the dopaminergic projection to the OPFC contributes to the regulation of inter-temporal choice. A quantitative method was used to compare inter-temporal choice in rats whose OPFC had been depleted of dopamine with that of sham-lesioned control rats. Under halothane anaesthesia, rats received injections of 6-hydroxydopamine into the OPFC (2 microg microl(-1), 0.5 microl, two injections in each hemisphere), or sham lesions (injections of the vehicle). They were trained to press two levers (A and B) for sucrose reinforcement (0.6 M) in discrete-trials schedules. In free-choice trials, a press on A resulted in delivery of 50 microl of the sucrose solution after a delay dA; a press on B resulted in delivery of 100 microl of the same solution after a delay dB. dB was increased progressively across successive blocks of six trials in each session, while dA was manipulated systematically across phases of the experiment. The indifference delay, dB(50) (value of dB corresponding to 50% choice of B) was estimated for each rat in each phase. Linear functions of dB(50) versus dA were derived, and the parameters of the function compared between the groups. Concentrations of monoamines in the OPFC were determined by high-performance liquid chromatography at the end of the experiment. In both groups, dB(50) increased linearly with dA (r2>0.9 in each case). The slope of the function was significantly steeper in the lesioned group than the sham-lesioned group, whereas the intercept did not differ significantly between the groups. When delays of 4 or 8 s were imposed on the smaller reinforcer, the lesioned rats showed greater tolerance of delay to the larger reinforcer (i.e. they exhibited longer values of dB(50)) than the sham-lesioned rats. Dopamine, noradrenaline and 5-hydroxytryptamine levels in the OPFC of the lesioned group were 20, 75 and 98% of those of the sham-lesioned group. The results indicate that dopaminergic afferents to the OPFC contribute to the regulation of inter-temporal choice behaviour due to their role in determining organisms' sensitivity both to reinforcer size and to delay of reinforcement.

S.28.01 5-HT approaches to anxiety: Making sense of animal studies

Wild running (WR) behavior of rats seen in response to intense acoustic stimulation of audiogenic seizure-paradigm is very similar to the panic flight and can be facilitated by subconvulsive doses of strychnine. The present work aimed to test whether antipanic procedures, such as dorsal periaqueductal gray (dPAG) lesion and imipramine treatments, affect the strychnine-facilitated WR. In study 1, six Wistar male adult rats with electrolytic lesion of dPAG had their WR completely blocked, whereas it was facilitated in 50% of sham-lesioned control rats by a dose of 0.5 mg/kg of strychnine administered intraperitoneal. This effect was not reproduced with a higher strychnine dose (1.0 mg/kg). In study 2, the effects of imipramine were investigated by testing 36 rats under a dose of strychnine that induces WR in 50% of subjects. They were assigned into three experimental groups: imipramine treatments of 5.0 and 10.0 mg/kg, and infusions of saline. All these treatments were subchronical with three intraperitoneal injections within 24 h. Imipramine (10.0 mg/kg) reduced the incidence of WR in comparison to the saline results. It is concluded that strychnine-facilitated WR is reduced by antipanic procedures and, therefore, can be viewed as a manifestation closely related to panic.

Antipanic procedures reduce the strychnine-facilitated wild running of rats

Wild running (WR) behavior of rats seen in response to intense acoustic stimulation of audiogenic seizure-paradigm is very similar to the panic flight and can be facilitated by subconvulsive doses of strychnine. The present work aimed to test whether antipanic procedures, such as dorsal periaqueductal gray (dPAG) lesion and imipramine treatments, affect the strychnine-facilitated WR. In study 1, six Wistar male adult rats with electrolytic lesion of dPAG had their WR completely blocked, whereas it was facilitated in 50% of sham-lesioned control rats by a dose of 0.5 mg/kg of strychnine administered intraperitoneal. This effect was not reproduced with a higher strychnine dose (1.0 mg/kg). In study 2, the effects of imipramine were investigated by testing 36 rats under a dose of strychnine that induces WR in 50% of subjects. They were assigned into three experimental groups: imipramine treatments of 5.0 and 10.0 mg/kg, and infusions of saline. All these treatments were subchronical with three intraperitoneal injections within 24 h. Imipramine (10.0 mg/kg) reduced the incidence of WR in comparison to the saline results. It is concluded that strychnine-facilitated WR is reduced by antipanic procedures and, therefore, can be viewed as a manifestation closely related to panic.

Behavioural sensitisation to repeated d-amphetamine: effects of excitotoxic lesions of the pedunculopontine tegmental nucleus

The pedunculopontine tegmental nucleus (PPTg) interacts with anatomical systems thought to be involved in mediating sensitisation of the locomotor response to repeated d-amphetamine. The PPTg has direct and indirect connections with the nucleus accumbens and prefrontal cortex, and also influences midbrain dopamine activity through direct projections to substantia nigra and ventral tegmental area. In this experiment, the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine was examined in rats bearing excitotoxic lesions of the PPTg, and sham-lesioned controls. Rats were given repeated d-amphetamine (1.5 mg/kg i.p.) treatment in an on–off procedure, with saline and d-amphetamine given on alternate days, such that rats received a total of seven d-amphetamine and seven saline treatments. Locomotor responses were measured in photocell cages. On the first day of d-amphetamine treatment, there was no difference between excitotoxin and sham-lesioned rats. Development of sensitisation to the locomotor stimulant effects of d-amphetamine was delayed in PPTg-lesioned rats, relative to the sham-lesioned control rats. However, there was no difference between lesion and control groups in the locomotion seen on saline-treatment days. These data suggest that the PPTg is involved in the development of behavioural sensitisation to the locomotor stimulant effects of repeated d-amphetamine, and indicate that traditional striatal circuitry models of the mechanisms underlying sensitisation should be extended to include the PPTg.

Area postrema lesions elevate NPY levels and decrease anxiety-related behavior in rats

Intracerebroventricular administration of neuropeptide Y (NPY) has been shown to reduce anxiety-like effects in rodents and also profoundly alter feeding. The area postrema-lesioned (APX) rat model of food motivated behavior overconsumes palatable foods and expresses significantly higher levels of NPY in the hypothalamus than sham-lesioned control rats. For this reason, we examined APX rats in the open field test, which is a standard measure of anxiety- or fear-related behavior and also investigated NPY mRNA levels in the hippocampus, amygdala and hypothalamus. We found that APX rats display reduced anxiety-like behavior in the open field test as indicated by spending increased time in the center of the field as opposed to the perimeter of the field. NPY mRNA levels were also found to be significantly elevated in the amygdala, hippocampus and arcuate nucleus of the hypothalamus of APX rats when compared to sham-lesioned rats. These results support the action of limbic NPY to reduce anxiety-like behavior in a rodent model that appears to express higher than normal NPY levels.

Postnatal glutamate-induced central nervous system lesions alter periodontal disease susceptibility in adult Wistar rats.

Inability to mount a suitable brain-neuroendocrine response to bacterial or other antigenic challenges has been found to play an important rôle in infectious and inflammatory disease susceptibility and progression, including periodontal disease. The present study was designed to determine the effects of glutamate administration to new-born Wistar rats on the development and progression of naturally occurring and ligature-induced periodontal disease in the rats as adults. Postnatal glutamate administration is known to permanently damage neurones in the hypothalamic arcuate nucleus. New-born rats were treated 1x daily subcutaneously with 2 mg/g of monosodium-L-glutamate (MSG) for 5 days from day 3 to 6. Control animals were injected with similar amounts of saline. Experimental ligature-induced periodontal disease was induced in the rats at the age of 12 weeks at maxillary right 2nd molar teeth. The contralateral maxillary left 2nd molars served as control teeth, and for assessment of naturally occurring periodontal disease. Disease progression was evaluated histometrically. The results revealed that the glutamate-lesioned rats developed significantly more periodontal tissue destruction compared to sham-lesioned control rats in both the ligated and non-ligated teeth. This study supports our recent findings indicating that inappropriate brain-neuroendocrine-immune regulation may play a rôle in periodontal disease susceptibility and progression.

Hippocampal lesions prevent trace eyeblink conditioning in the freely moving rat

The effect of hippocampal aspiration lesions on trace eyeblink conditioning was examined in young, freely-moving F1 hybrid rats (Fisher 344×Brown Norway). Rats which received either bilateral neocortical or bilateral hippocampal aspiration lesions were compared with each other or with sham lesioned control rats. The rats were trained with a 250 ms tone conditioning stimulus (CS), a 250 ms stimulus free trace interval and a 100 ms corneal airpuff unconditioned stimulus (US). Rats with lesions of the hippocampus were significantly impaired relative to the neocortical and sham lesioned control rats. Analyses of different behavioral parameters (e.g. percent conditioned responses, amplitude, and area of response) indicated that all of the measures for the conditioned response were significantly impaired by the hippocampal lesion. The unconditioned response was not significantly affected by the lesion, and there was no significant difference among the groups after 2 days of subsequent conditioning with the delay paradigm (zero trace interval). We conclude that the hippocampus is required for rats to learn the association between a tone CS and an airpuff US when a 250 ms trace interval is interposed between the two stimuli.

Effect of destruction of the 5-hydroxytryptaminergic pathways on temporal memory: quantitative analysis with a delayed interval bisection task.

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on memory for duration, using a delayed interval bisection task. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a "correct' response, reinforcer delivery. When > 90% correct choices had been attained, an 8-s (phase I) or a 12-s (phase II) delay was interposed between stimulus offset and lever presentation in 50% of the trials, and probe trials (10% of both non-delay and delay trials) were introduced in which the light was presented for intermediate durations. Logistic functions were derived relating percent choice of lever B to stimulus duration. In both groups, the imposition of post-stimulus delays displaced the bisection point (duration yielding 50% choice of lever B) towards longer durations; this effect was significantly greater in the lesioned group than in the control group. Imposition of post-stimulus delays resulted in increases in the Weber fraction, which did not differ significantly between the two groups. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered.

Effect of destruction of the 5-hydroxytryptaminergic pathways on the acquisition of temporal discrimination and memory for duration in a delayed conditional discrimination task.

This experiment examined the effect of destruction of the ascending 5-hydroxytryptaminergic (5HTergic) pathways on the acquisition of a temporal discrimination and on memory for duration, using a delayed conditional discrimination task. In phase I, rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats, were trained in a series of discrete trials to press lever A following a 2-s presentation of a light stimulus, and lever B following an 8-s presentation of the same stimulus. Following stimulus offset, a response on a panel placed midway between the two levers was required in order to initiate lever presentation; a single response on either lever resulted in withdrawal of both levers and, in the case of a "correct" response, reinforcer delivery. Both groups gradually acquired accurate discrimination, achieving > 90% correct choices within 20-30 sessions; the lesioned group acquired accurate performance significantly faster than the control group. In phase II, delays were interposed between stimulus offset and lever presentation in 50% of the trials (2, 4, 8, 16 and 32 s; 10% of trials in each case). Accuracy declined as a function of post-stimulus delay in both groups, and there was no significant difference between the performances of the two groups. Both groups showed an increasing tendency to respond on lever A following longer post-stimulus delays ("choose-short" effect); this effect was somewhat enhanced in the lesioned group. The levels of 5HT and 5-hydroxyindoleacetic acid were reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered.

Facilitated acquisition of a temporal discrimination following destruction of the ascending 5-hydroxytryptaminergic pathways

This experiment examined the effect of destroying the 5-hydroxytryptaminergic (5HTergic) pathways on the acquisition and performance of discrimination between two brief time intervals. Rats that had received injections of 5,7-dihydroxytryptamine into the dorsal and median raphe nuclei, and sham-lesioned control rats were trained in a series of discrete trials to press lever A following a 200-ms presentation of a light stimulus and lever B following an 800-ms presentation of the same stimulus. Both groups gradually acquired accurate performance, attaining 80%-85% accuracy by the end of 40 sessions. The lesioned group learnt the task significantly faster than the control group. When stable performance had been attained, "probe" trials were introduced in which the light was presented for intermediate durations. Both groups showed sigmoid functions relating percent choice of lever B to log stimulus duration. The bisection point (duration corresponding to 50% choice of lever B) did not differ significantly between the two groups; however, the Weber fraction was significantly smaller in the lesioned group than in the control group. The levels of 5HT and 5-hydroxy-indole-acetic acid were markedly reduced in the brains of the lesioned rats, but the levels of noradrenaline and dopamine were not altered. The results indicate that destruction of the 5HTergic pathways facilitates acquisition of a temporal discrimination. The lack of an effect of the lesion on the bisection point contrasts with our previous finding using longer stimulus durations; it is suggested that different behavioural processes may underlie millisecond-range and second-range temporal discrimination, and that these may be differently affected by 5HT depletion.

Novel diet consumption and body weight gain are reduced in rats chronically infused with lithium chloride: Mediation by the chemosensitive area postrema

The effects of chronic lithium chloride infusions on consumption of, and subsequent preferences for, a novel diet were examined in rats with ablations of the area postrema (AP) and sham-lesioned control rats. Osmotic minipumps (Alza), filled with a saturated aqueous solution of LiCl (63 g/100 ml), were implanted in the peritoneal cavity of half of the lesioned rats ( n = 9) and half of the control rats ( n = 8). The remaining rats received empty pumps ( n = 9 and n = 7 for lesioned and controls, respectively). The LiCl or sham drug phase was paired with free access to a highly palatable novel diet (AIN diet) during a 7-day conditioning period. Subsequent preferences for the novel diet relative to a familiar diet (ground Purina lab pellets) were determined using a two-food choice procedure. The only group to show a persistent and significant reduction in novel food consumption during the conditioning phase was the sham-lesioned group infused with LiCl ( p< 0.01). This group also exhibited a marked aversion for the novel diet, indicative of a conditioned food aversion (CFA), during the preference tests. No significant differences in novel diet consumption or in novel diet preference were found between the two AP-lesioned groups. This study provides evidence that anorexia and CFAs to a novel diet, induced with chronic infusions of lithium, are abolished by destruction of the chemosensitive area postrema.

Bilateral midbrain transections block the behavioral effects of cholecystokinin on feeding and exploration in rats

The mechanism by which peripherally administered cholecystokinin (CCK) reduces feeding and exploration involves a sensory feedback pathway from the gastrointestinal regions, via the vagus nerve 7,22,31 through the nucleus tractus solitarius (NTS) 9. Bilateral dorsal midbrain transections rostral to the NTS abolish the ability of CCK to reduce food consumption, decrease exploratory approaches, and increase pauses of behavioral inactivity, as compared to these actions of CCK in normal and sham-lesioned control rats, suggesting that ascending NTS fibers are a necessary component in this feedback system.

Effects of discrete lesions of the sexually dimorphic nucleus of the preoptic area or other medial preoptic regions on the sexual behavior of male rats

The sexually dimorphic nucleus of the rat medial preoptic area (SDN-POA) has a volume five times larger in the adult male compared with that of the adult female. In the present study, the effects of discrete electrolytic destruction of the SDN-POA or other specific medial preoptic (MPOA) regions on masculine sexual behavior were determined in adult, sexually experienced male rats. Small lesions encompassing the SDN-POA had no effect on the maintenance of copulatory behavior. Lesions of similar size placed within the ventral or anterio-dorsal MPOA also did not consistently affect the display of masculine sexual behavior. However, animals that received small lesions within their dorsal MPOA showed a substantial, long-term decrease in number of mounts, intromissions, and ejaculations compared to these parameters in sham-lesioned control rats, thus indicating a lesion-induced disruption of those neural mechanisms mediating these behaviors. Collectively these data suggest that the SDN-POA is not critical for a full expression of male sexual behavior and that the dorsal MPOA may be more important than other MPOA regions for copulatory behavior.

Medial hypothalamic lesions in the rat enhance reactivity and mouse killing but not social aggression

In rats subjected to lesions of the medial hypothalamus, 8 of 11 animals became mouse killers and all manifested some degree of hyperreactivity to the experimenter. When introduced as intruders into a mixed sex colony group, the lesioned rats did not manifest piloerection nor did they emit flank attacks characteristic of social aggressive behavior. However, the lesioned animals did respond to the attacks of the resident male rats with significantly more counterattacks and biting than did sham-lesioned control rats. Spontaneous mouse killing rats also failed to show a level of social aggressive behavior significantly greater than that of sham-operated control rats, but the spontaneous mouse killers did kill rat pups in the colony groups. Alpha-male rats when introduced as an intruder into a colony group did exhibit piloerection and emit flank attacks characteristic of social aggressive behavior. These results demonstrate that the mouse killing and heightened reactivity associated with medial hypothalamic lesions do not represent an indiscriminant release of all forms of agonistic behavior.

Ventromedial hypothalamic lesions elevate basal and cephalic phase gastric acid output

With the use of a new technique for the measurement of gastric acid output in the rat, this study identifies ventromedial hypothalamic (VMH) lesion-induced changes in gastric acid secretion. Basal and cephalic phase gastric acid secretion were monitored in VMH- and sham-lesioned control rats on days 1, 5, 9, 13, and 17 postlesion as well as after the full development of obesity. VMH lesions resulted in increases of both phases of secretion. The magnitude of hypersecretion in lesioned rats developed with time and was fully developed by day 9 postlesion. The hypersecretion did not require a hyperphagia or weight gain, but its degree correlated with subsequent weight gain. These data, in conjunction with a review of VMH lesion effects on insulin secretion, suggest a widespread effect of VMH lesions on visceral secretory responses. The relevance of these data to the etiology of the VMH syndrome is discussed.