Postlesion Week Research Articles

Long-Term Motor Cortical Electrical Stimulation Ameliorates 6-Hydroxydopamine-Induced Motor Dysfunctions and Exerts Neuroprotective Effects in a Rat Model of Parkinson's Disease.

ObjectiveCortical electrical stimulation (CES) can modulate cortical excitability through a plasticity-like mechanism and is considered to have therapeutic potentials in Parkinson’s disease (PD). However, the precise therapeutic value of such approach for PD remains unclear. Accordingly, we adopted a PD rat model to determine the therapeutic effects of CES. The current study was thus designed to identify the therapeutic potential of CES in PD rats.MethodsA hemiparkinsonian rat model, in which lesions were induced using unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle, was applied to identify the therapeutic effects of long-term (4-week) CES with intermittent theta-burst stimulation (iTBS) protocol (starting 24 h after PD lesion observation, 1 session/day, 5 days/week) on motor function and neuroprotection. After the CES intervention, detailed functional behavioral tests including gait analysis, akinesia, open-field locomotor activity, apomorphine-induced rotation as well as degeneration level of dopaminergic neurons were performed weekly up to postlesion week 4.ResultsAfter the CES treatment, we found that the 4-week CES intervention ameliorated the motor deficits in gait pattern, akinesia, locomotor activity, and apomorphine-induced rotation. Immunohistochemistry and tyrosine hydroxylase staining analysis demonstrated that the number of dopamine neurons was significantly greater in the CES intervention group than in the sham treatment group.ConclusionThis study suggests that early and long-term CES intervention could reduce the aggravation of motor dysfunction and exert neuroprotective effects in a rat model of PD. Further, this preclinical model of CES may increase the scope for the potential use of CES and serve as a link between animal and PD human studies to further identify the therapeutic mechanism of CES for PD or other neurological disorders.

Neurochemical excitation of thoracic propriospinal neurons improves hindlimb stepping in adult rats with spinal cord lesions

Using an in vitro neonatal rat brainstem–spinal cord preparation, we previously showed that cervicothoracic propriospinal neurons contribute to descending transmission of the bulbospinal locomotor command signal, and neurochemical excitation of these neurons facilitates signal propagation. The present study examined the relevance of these observations to adult rats in vivo. The first aim was to determine the extent to which rats are able to spontaneously recover hindlimb locomotor function in the presence of staggered contralateral hemisections (left T2–4 and right T9–11) designed to abolish all long direct bulbospinal projections. The second aim was to determine whether neurochemical excitation of thoracic propriospinal neurons in such animals facilitates hindlimb stepping. In the absence of intrathecal drug injection, all animals (n=24) displayed some degree of hindlimb recovery ranging from weak ankle movements to brief periods of unsupported hindlimb stepping on the treadmill. The effect of boluses of neurochemicals delivered via an intrathecal catheter (tip placed midway between the rostral and caudal thoracic hemisections) was examined at post-lesion weeks 3, 6 and 9. Quipazine was particularly effective facilitating hindlimb stepping. Subsequent complete transection above the rostral (n=3) or caudal (n=2) hemisections at week 9 had no consistent effect on drug-free locomotor performance, but the facilitatory effect of drug injection decreased in 4/5 animals. Two animals underwent complete transection at T3 as the first and only surgery and implantation of two intrathecal catheters targeted to the mid-thoracic and lumbar regions, respectively. A similar facilitatory effect on stepping was observed in response to drugs administered via either catheter. The results indicate that partial spontaneous recovery of stepping occurs in adult rats after abolishing all long direct bulbospinal connections, in contrast to previous studies suggesting that hindlimb stepping after dual hemisections either does not occur or is observed only if the second hemisection surgery is delayed relative to the first. The results support the hypothesis that artificial modulation of propriospinal neuron excitability may facilitate recovery of motor function after spinal cord injury. However, whether this facilitation is due to enhanced transmission of a descending locomotor signal or is the result of excitation of thoracolumbar circuits independent of supraspinal influence, requires further study.

The reactivation of somatosensory cortex and behavioral recovery after sensory loss in mature primates.

In our experiments, we removed a major source of activation of somatosensory cortex in mature monkeys by unilaterally sectioning the sensory afferents in the dorsal columns of the spinal cord at a high cervical level. At this level, the ascending branches of tactile afferents from the hand are cut, while other branches of these afferents remain intact to terminate on neurons in the dorsal horn of the spinal cord. Immediately after such a lesion, the monkeys seem relatively unimpaired in locomotion and often use the forelimb, but further inspection reveals that they prefer to use the unaffected hand in reaching for food. In addition, systematic testing indicates that they make more errors in retrieving pieces of food, and start using visual inspection of the rotated hand to confirm the success of the grasping of the food. Such difficulties are not surprising as a complete dorsal column lesion totally deactivates the contralateral hand representation in primary somatosensory cortex (area 3b). However, hand use rapidly improves over the first post-lesion weeks, and much of the hand representational territory in contralateral area 3b is reactivated by inputs from the hand in roughly a normal somatotopic pattern. Quantitative measures of single neuron response properties reveal that reactivated neurons respond to tactile stimulation on the hand with high firing rates and only slightly longer latencies. We conclude that preserved dorsal column afferents after nearly complete lesions contribute to the reactivation of cortex and the recovery of the behavior, but second-order sensory pathways in the spinal cord may also play an important role. Our microelectrode recordings indicate that these preserved first-order, and second-order pathways are initially weak and largely ineffective in activating cortex, but they are potentiated during the recovery process. Therapies that would promote this potentiation could usefully enhance recovery after spinal cord injury.

Progressive impairment in motor skill learning at 12 and 20 weeks post 6-OHDA- SNc lesion in rats

Deficiency in skilled motor activity is primarily attributed to the loss of dopaminergic neurons in the pars compacta of substantia nigra (SNc), which can be detected by performance of the rotarod test. Previous reports have demonstrated impaired skilled motor behavior in rats during the pre-motor stage of Parkinson’s disease (PD) (3–8 weeks post 6-OHDA lesion of striatum). We studied skilled motor learning in 6-hydroxydopamine (6-OHDA) SNc lesion rats at 12 and 20 weeks by rotarod task after providing sufficient training to give allowance for ageing (3 sessions/day for 14 consecutive days). On each day, the stay duration on rotarod was noted and compared between the groups (Group 1 = Control, Group 2 = Post lesion (PL) week 12, Group 3 = PL week 20). In Group 2 rats, the duration of stay on rotarod gradually increased from day 1 through 7 {day 7 = 193.1 (81.8–247.4) vs. control group day 7 = 202.1 (87.7–279.8), p = 0.771} and declined thereafter. While, the stay duration in Group 3 rats remained lower {day 7 = 32.5 (20.4–52.1), p = 0.011} than that of the control rats throughout the study period. The results of our study suggest a slower brief learning of skilled motor tasks at post lesion week 12 whereas no learning at all at post-lesion week 20.

Cellular and molecular bases of neuroplasticity: brainstem effects after cochlear damage

After a cochlear lesion or auditory nerve damage, afferent connections from auditory ganglia can be highly altered. This results in a clear reduction of auditory input and an alteration of connectivity of terminals on cochlear nuclei neurons. Such a process could stimulate the reorganization of the neural circuits and neuroplasticity. Cochlea removal has been demonstrated to be a good model in which to analyse brainstem neuroplasticity, particularly with regard to the cochlear nuclei. After cochlea removal three main periods of degeneration and regeneration were observed. Early effects, during the first week post lesion, involved acute degeneration with nerve ending oedema and degeneration. During the second and, probably, the third post lesion weeks, degeneration was still present, even though a limited and diffuse expression of GAP-43 started. Around 1 month post lesion, degeneration at the cochlear nuclei progressively disappeared and a relevant GAP-43 expression was found. We conclude that neuroplasticity leads neurons to modify their activity and/or their synaptic tree as a consequence of animal adaptation to learning and memory. For the human being neuroplasticity is involved in language learning and comprehension, particularly the acquisition of a second language. Neuroplasticity is important for therapeutic strategies, such as hearing aids and cochlear implants.

Cellular and molecular bases of neuroplasticity: brainstem effects after cochlear damage

After a cochlear lesion or auditory nerve damage, afferent connections from auditory ganglia can be highly altered. This results in a clear reduction of auditory input and an alteration of connectivity of terminals on cochlear nuclei neurons. Such a process could stimulate the reorganization of the neural circuits and neuroplasticity. Cochlea removal has been demonstrated to be a good model in which to analyse brainstem neuroplasticity, particularly with regard to the cochlear nuclei. After cochlea removal three main periods of degeneration and regeneration were observed. Early effects, during the first week post lesion, involved acute degeneration with nerve ending oedema and degeneration. During the second and, probably, the third post lesion weeks, degeneration was still present, even though a limited and diffuse expression of GAP-43 started. Around 1 month post lesion, degeneration at the cochlear nuclei progressively disappeared and a relevant GAP-43 expression was found. We conclude that neuroplasticity leads neurons to modify their activity and/or their synaptic tree as a consequence of animal adaptation to learning and memory. For the human being neuroplasticity is involved in language learning and comprehension, particularly the acquisition of a second language. Neuroplasticity is important for therapeutic strategies, such as hearing aids and cochlear implants.

Primary afferent terminal sprouting after a cervical dorsal rootlet section in the macaque monkey.

We examined the role of primary afferent neurons in the somatosensory cortical "reactivation" that occurs after a localized cervical dorsal root lesion (Darian-Smith and Brown [2000] Nat. Neurosci. 3:476-481). After section of the dorsal rootlets that enervate the macaque's thumb and index finger (segments C6-C8), the cortical representation of these digits was initially silenced but then re-emerged for these same digits over 2-4 postlesion months. Cortical reactivation was accompanied by the emergence of physiologically detectable input from these same digits within dorsal rootlets bordering the lesion site. We investigated whether central axonal sprouting of primary afferents spared by the rhizotomy could mediate this cortical reactivation. The cortical representation of the hand was mapped electrophysiologically 15-25 weeks after the dorsal rootlet section to define this reactivation. Cholera toxin subunit B conjugated to horseradish peroxidase was then injected into the thumb and index finger pads bilaterally to label the central terminals of any neurons that innervated these digits. Primary afferent terminal proliferation was assessed in the spinal dorsal horn and cuneate nucleus at 7 days and 15-25 postlesion weeks. Labeled terminal bouton distributions were reconstructed and the "lesion" and control sides compared within each monkey. Distributions were significantly larger on the side of the lesion in the dorsal horn and cuneate nucleus at 15-25 weeks after the dorsal rootlet section, than those mapped only 7 days postlesion. Our results provide direct evidence for localized sprouting of spared (uninjured) primary afferent terminals in the dorsal horn and cuneate nucleus after a restricted dorsal root injury.

The effects of intracortical endothelin-1 injections on skilled forelimb use: implications for modelling recovery of function after stroke

Different methods of inducing experimental brain lesions can result in distinct neuropathological sequelae. This could be of consequence in attempts to establish animal models of recovery of function following stroke, as differences in the progression of experimental lesion pathology may have an impact on the magnitude and rate of recovery of function observable with any particular lesioning method. In the present study, a novel method of producing a focal ischaemic lesion by intracortical microinjection of endothelin-1 (ET-1) was compared with excitotoxic (microinjection of quinolinic acid) and mechanical (aspiration) lesioning procedures. Lesions were unilateral and were targeted at the forelimb representation zone in sensorimotor cortex. It was found that all three types of lesion had an essentially identical effect with regard to reaching accuracy in a paw-reaching task. All lesioned animals displayed a similar, significant long-term deficit in reaching accuracy and limited degree of recovery relative to sham animals. Off-line analysis of the performance of animals during post-lesion week 9 indicated that animals in each lesion group also displayed a similar deficit. The current results suggest that the spontaneous behavioural consequences of a unilateral lesion of FL in the rat appear to be independent of the nature of lesion production. However, the increased face validity of an ET-1-induced lesion, coupled with the ease of control of lesion placement and extent offered by this technique make for a potentially important animal model for research into drug effects on recovery of function following stroke.

Anxiolysis followed by anxiogenesis relates to coping and corticosterone after medial prefrontal cortical damage in rats

Medial prefrontal cortex (MPFC) damage causes profound behavioral and neuroendocrine alterations. However, many reports have been inconsistent regarding the direction of these effects. We hypothesized that the lesion recovery stage might be a key factor generating discrepancies. To examine changes over time following ibotenic acid lesion in the ventral part of the MPFC, behavioral and endocrine testing was conducted on the second and the fifth week after lesioning. On the second post-lesion week, bilaterally lesioned animals increased social interaction and swimming scores and their corticosterone response to restraint was exaggerated as compared with shams. On the fifth post-lesion week, social interaction and swimming scores were diminished in bilaterally lesioned animals; their basal plasma corticosterone was enhanced, while their corticosterone increase under restraint was blunted relative to shams. These results reveal that the emotional and endocrine responses to stress vary as a function of time following MPFC lesion, which may help to reconcile conflicting reports on effect direction. The role of the MPFC in anxiety, ability to cope with stress and adrenal regulation is also discussed.

Lesions of the medial prefrontal cortex and sexual behavior in the male rat

Lesions of the cerebral cortex near the midline in the frontal region appearing to destroy most of the cingulate cortex and adjacent prefrontal areas had profound effects on male rat sexual behavior. At the first postoperative tests, one week after lesion, the mount and intromission latencies were extremely long (> 60 min). They continued elevated at every fortnightly test until postlesion week 13, when they were no longer different from controls. However, the proportion of animals that intromitted or ejaculated was reduced at this time. The lesion had a slight effect on the number of intromissions and on the intromission ratio, but did not reliably modify other parameters of sexual behavior in those males that copulated after operation. These data suggest that the medial prefrontal cortex is important for the initiation of sexual behavior but less so for its execution. It is proposed that the elaboration and/or interpretation of environmental stimuli are rendered deficient by the lesion. Consequently, sexual behavior is activated only with difficulty. This coincides with the arousal hypothesis proposed by Beach [8]. There appears to exist a spontaneous recovery of the mechanisms responsible for the activation of sex behavior because the lesioned group was not different from the sham or intact groups 13 weeks postlesion. Remaining cortical tissue or other brain structures may compensate for the initial deficiencies. However, the lesion's effect on intromission behavior did not diminish with time. This could suggest that possible motor deficiencies produced by the lesion are irreversible.

Importance of cholinergic, GABAergic, serotonergic and other neurons in the medial medullary reticular formation for sleep-wake states studied by cytotoxic lesions in the cat

Previous evidence has suggested that neurons in the medial medullary reticular formation play a critical role in the modulation of forebrain and spinal cord activity that occurs during the sleep-waking cycle and particularly in association with the state of paradoxical sleep. The importance of these neurons, including cholinergic, serotonergic and GABAergic cells [Holmes C. J. et al. (1994) Neuroscience 62, 1155–1178] for sleep-wake states was investigated after their destruction with the neurotoxin quisqualic acid injected into the medullary gigantocellular and magnocellular tegmental fields in cats. To assess the effects of the neuronal loss, polygraphic recording and behavioural observations were performed in baseline and for three weeks after the lesion, and the changes in these measures were correlated with the volume of destruction of medullary regions and the numbers of chemically identified cells within those regions. Following the cytotoxic lesions, which affected ∼60% of the medullary gigantocellular and magnocellular tegmental fields, there was a significant reduction in the amount of paradoxical sleep (to a mean of 64% of baseline) during the first postlesion week, that recovered variably across cats in the second and third weeks. There was little to no change in the amount or organization of waking and slow wave sleep. The individually variable amounts of postlesion paradoxical sleep were correlated positively with the number of surviving cholinergic cells, negatively with the number of surviving serotonergic cells and positively with the ratio of surviving cholinergic or GABAergic cells to serotonergic cells. The most marked effect of the lesion was a substantial increase in the amplitude of the nuchal electromyogram during slow wave sleep (to 198%) and paradoxical sleep (to 378% of baseline in the first postlesion week). The increase in muscle tone was associated with movements of the head, neck or limbs during paradoxical sleep. Although, in some cats, the abnormal neck muscle tone decreased with time, limb movements continued to occur during paradoxical sleep for the duration of the experiment. The ratio of the total number of remaining cholinergic or GABAergic cells to serotonergic cells correlated negatively with the increased muscle tone and/or movements. It was concluded that the neurons of the medial medullary reticular formation contribute to, but are not necessary for, the generation of paradoxical sleep, and have particular importance for the regulation of muscle tone and inhibition of movement during this state. From correlative evidence, it appears that medullary cholinergic neurons may play a facilitatory role, whereas serotonergic cells would play an inhibitory role in the generation of paradoxical sleep and associated motor inhibition. The relative numbers and presumed activities of these putative paradoxical sleep-ON versus paradoxical sleep-OFF cell populations appears to be most important for the appearance of the state and muscle atonia. Intrinsic GABAergic neurons may play an intermediary role, with their local projections being potentially important for inhibiting paradoxical sleep-OFF cells but also for disinhibiting paradoxical sleep-ON cells within the medial medullary reticular formation and raphe.

Effects of nucleus basalis lesion on muscarinic receptor subtypes

The cholinergic system in the central nervous system is an important component of the neural circuitry of learning, memory and cognition. A decline of cholinergic innervation in the human brain is a characteristic feature of dementia of Alzheimer's type. In this study, changes in cholinergic markers were studied after a unilateral lesion of the nucleus basalis magnocellularis (nbM). Acetylcholinesterase (AChE) histochemistry showed a loss of cortical AChE-containing neurons, and choline acetyltransferase (ChAT) immunohistochemistry demonstrated a loss of cholinergic cells in nbM. The localizations of muscarinic M1 and M2 receptors using [3H]pirenzepine ([3H]PZ) and [3H]AF-DX 384, respectively, were studied by quantitative autoradiography 1, 2, 4 and 6 weeks following unilateral ibotenic acid lesion of nbM. A significant decrease in [3H]PZ binding sites was observed at postlesion week 1 in the parietal and temporal cortices. The decrease in [3H]AF-DX 384 binding sites on the lesioned side was observed throughout frontal, parietal and temporal cortices after postlesion week 1, with a significant increase after 6 weeks, possibly as result of loss of presynaptic receptors and upregulation of postsynaptic ones. Moreover, laminar distribution after nbM lesion shows that M1 and M2 receptor binding sites are more affected in superficial layers (I,II,III) than in the deep layers (IV,V,VI), depending on ligand, postlesion period and cortical region. Furthermore, nbM lesion causes a higher deficit of M2 receptors than of M1 receptors. These data suggest the existence of a presynaptic population as well as a postsynaptic population of M1 and M2 receptors which are differently affected after unilateral nbM lesion.

Delayed matching-to-sample performance by rats in a new avoidance-motivated maze: Response to scopolamine and fimbria-fornix lesions

A new avoidance-motivated detour-maze in which memory for an immediately preceding sample event could be assessed was evaluated by testing seven 6-month-old male F-344 rats with a delayed matching-to-sample (DMTS) paradigm. Rats first received extensive pretraining with this paradigm over several months and after a minimum of 1,390 choice-trials demonstrated great proficiency in this maze. Studies were then conducted to establish cholinergic and hippocampal involvement in the DMTS task by using drug manipulations (scopolamine and physostigmine), and after lesions to the fimbria-fornix (FF) pathway. A high dose (1.0 mg/kg) of scopolamine but not a low dose (0.3 mg/kg) significantly interfered with choice accuracy as measured by errors and trials to criterion; physostigmine (0.01 and 0.03 mg/kg) had no significant effect; and fimbria lesions significantly disrupted both choice accuracy and runtime performance. Disruption was most pronounced on difficult problems (different paths to the goal). After lesions only, considerable within-trial perseverative errors occurred during the early postlesion weeks on four difficult problems from among the 18 tested. Results were discussed in terms of (a) specificity of this disruption, (b) indications of proactive interference effects, and (c) the movement-related excitation component of maze learning. The present results accord with earlier findings of disruption by scopolamine and FF lesions in a 14-unit T-maze, both mazes having similar performance requirements of shock avoidance and multiple 90-degree turns along the paths to the goal. The present results affirm that this new detour maze provides a viable approach for assessing cognitive performance in a within-subjects design and thereby offers new possibilities for testing various aspects of cognitive processing, particularly for aged rodent models, in a complex aversive situation.

NGF receptor (p75)-immunoreactivity within hypoglossal motor neurons following axotomy in monkeys

The expression of the p75 nerve growth factor receptor (NGFR) was examined in Rhesus and Cebus monkeys following complete unilateral transections of the hypoglossal nerve. In unoperated and sham-lesioned monkeys, NGF receptor-immunoreactivity was always undetectable within hypoglossal motor neurons. In contrast, monkeys receiving unilateral transections of the hypoglossal nerve displayed numerous NGFR-immunoreactive neurons within ipsilateral hypoglossal motor neurons 1 week post-lesion. The peak expression of NGFR-immunoreactive hypoglossal neurons was seen 4 weeks following the lesion and although fewer, these neurons were still observed in large numbers 10 weeks post-lesion. By 16 weeks post-lesion only a few NGFR-immunoreactive motor neurons were observed. A small number of NGF receptor-immunoreactive neurons were also seen within the contralateral hypoglossal nucleus at post-lesion weeks 4 and 10. These data demonstrate that adult hypoglossal motor neurons express detectable levels of p75 nerve growth factor receptor following hypoglossal nerve transection in monkeys in a manner similar to that previously reported in non-primate species. The synthesis of p75 NGF receptors in these neurons may represent a regeneration-mediated re-expression of NGF receptors which only normally occurs during development.

Attenuation of nucleus basalis of Meynert lesion-induced cholinergic deficits by nerve growth factor

Nerve growth factor (NGF) was administered into either the lateral ventricle or into the basal forebrain of n. basalis of Meynert (nbM) lesioned rats. Rats received either continuous infusion of 5 μg of 7S NGF per day for 28 days, or 5 μg of 7S NGF on 4 occasions distributed evenly during the first two post-lesion weeks. The administration of NGF reduced lesion-induced cortical cholinergic marker deficits by approximately 50%, irrespective of the locus or mode of NGF administration. Thus NGF is able to attenuate lesion-induced cholinergic deficits across a range of treatment and lesion conditions.

Aberrant phosphorylation of neurofilaments accompanies transmitter-related changes in rat septal neurons following transection of the fimbria-fornix

Lesions of the fimbria-fornix (FF) have been reported to cause retrograde changes in neurons of the medial septal nucleus (MSN). To analyze the nature and time course of these events, we investigated changes in cytoskeletal elements (phosphorylated and nonphosphorylated neurofilament (NF) proteins) and transmitter-related enzymes (choline acetyltransferase (ChAT) in MSN neurons following FF transection. During the first week postlesion, ChAT immunoreactivity and size of many perikarya were reduced. Irregular, swollen cholinergic fibers appeared first at postlesion day 2 in caudal septum and soon spread rostrally, reaching rostral septum by day 7. A few perikarya developed abnormal accumulations of phosphorylated NFs. At postlesion days 7–10, many neurons did not stain for ChAT. Phosphorylated NFs were present in many perikarya. At this time, cell loss was apparent in Nissl-stained material. Cholinergic cell loss continued through postlesion week 6–8 but at a much slower rate than during the first week. Phosphorylated NF accumulations in MSN perikarya persisted until postlesion week 6, disappearing thereafter. Double-immunostaining procedures showed that MSN neurons expressed both ChAT and phosphorylated NF immunoreactivity at postlesion day 3; however, at days 7 and 14, cells that accumulated phosphorylated NFs did not stain for ChAT. The results of this study indicate that FF transection leads to perikaryal shrinkage with loss of ChAT immunoreactivity, perikaryal phosphorylation of NFs, cholinergic fiber abnormalities, and cell loss. Recent evidence suggests that reduction of transmitter markers and aberrant phosphorylation of NFs may be involved in the pathogenesis of several neurodegenerative disorders, including Alzheimer's disease. Therefore, FF transection provides a useful animal model for further investigations of complex disorders of the central nervous system that involve degeneration of transmitter-specific pathways.

Mesolimbic dopamine and early post-6-OHDA lesion enhanced responses to d-amphetamine

Bilateral lesions of mesolimbic dopamine (DA) reliably produce an attenuated response to amphetamine's locomotor stimulatory effects when administered after two weeks of surgical recovery. Several studies have revealed enhanced amphetamine-induced hyperactivity during the first postlesion week, however. In the present study, animals with bilateral 6-OHDA lesions of nucleus accumbens and olfactory tubercle DA showed an exaggerated response to 1.0 mg/kg amphetamine during this early period but were hypoactive in the absence of drug treatment. Neurochemical assay at 5 days revealed increased DA metabolism in the tubercle. Shifting patterns of postlesion amphetamine response under conditions of reduced mesolimbic DA are suggestive of dynamic adaptations in nondopaminergic systems.

Spontaneous EEG spikes in the normal hippocampus. IV. Effects of medial septum and entorhinal cortex lesions

Spontaneous EEG spikes (SPKs) were recorded from the CA1 region of the dorsal hippocampus in normal rats during behavioral states not accompanied by rhythmical slow activity (RSA) such as awake immobility and slow wave sleep. The present experiment was designed to examine the effects of large electrolytic lesions of the 2 major hippocampo-petal systems, medial septum (MS) and entorhinal cortex (EC), on spontaneous SPK activity. MS lesions, while completely abolishing RSA, did not eliminate SPKs or change their behavioral correlates. SPKs were still suppressed during behaviors (walking, head movement, etc.) normally associated with RSA. However, SPK frequency was approximately halved after MS lesions. Total bilateral EC lesions did not, in general, change SPKs or RSA unless abnormal hippocampal activities persisted over the first post-lesion week during which most of the recordings were made. Laminar profiles of SPKs in both MS- and EC-lesioned rats showed a normal pattern; small positivity in stratum oriens, large negativity in stratum radiatum and polarity reversal around stratum pyramidale. These results suggest that (1) neither medial septal input nor entorhinal cortical input to the hippocampus is necessary for the generation of SPKs, and (2) SPK suppression still occurs in the absence of these inputs during behaviors normally associated with RSA. The possibility remains, however, that in intact animals these inputs do influence SPK activity in a behavior-dependent manner.

Frontal decortication and adaptive changes in striatal cholinergic neurons in the rat

Interruption of the corticostriatal pathway by undercutting the cortex resulted in a reduction of glutamate uptake by 55% and in a depression of acetylcholine (ACh) synthesis by 30% in striatum after two postlesion weeks without affecting the content of ACh and choline, the specific binding of [ 3H]dexetimide to muscarinic receptors, the activity of choline acetyltransferase and the levels of noradrenaline, serotonin, dopamine and 3,4-dihydroxyphenylacetic acid. The influence of this excitatory pathway on striatal cholinergic neuropharmacology was investigated. It was found that the effect of a number of agonists (R-apomorphine, bromocriptine, lisuride, quinpirole, JL-14389, 2-chloroadenosine, oxotremorine and methadone), capable of depressing cholinergic activity in the striatum through receptor-mediated responses — reflected as an increase in ACh content — is operative only when the corticostriatal pathway is intact. By contrast, antagonists capable of decreasing ACh content, i.e. the typical neuroleptics pimozide, haloperidol and the atypical ones clozapine, l-sulpiride, as well as the anti-muscarinic agent scopolamine, were not influenced by the lesion. The possibility that the lesion non-specifically damaged striatal cells on which the agonists, but not the antagonists acted was excluded by results showing, firstly, that the increase in striatal ACh elicited by the ACh precursor, choline, was not blocked by decortication, and secondly, that the degeneration of the corticostriatal neurons did not prevent the ACh-increasing effect of bromocriptine, a long-acting ergot alkaloid, when sufficient time was allowed for the drug to act. It was furthermore possible to restore the inhibitory action of apomorphine of cholinergic neurons either by short-term chemical lesion of the nigrostriatal dopaminergic input or by the administration of choline. The results suggest that the deafferentiated cholinergic neurons, being already inhibited by the loss of the excitatory input, cannot further be depressed by drugs that slow down their activity and their ACh turnover rate. Finally, some comments on the relationship between the dopaminergic, cholinergic and excitatory inputs in the striatum will be given.

Ventromedial hypothalamic lesions in rats: Gradual elevation of body weight set-point

Bilateral electrolytic (DC) or radiofrequency (RF) lesions of the ventromedial hypothalamic (VMH) area produced two abnormal stages of fattening in adult female rats. Following a negatively-accelerated, curvilinear phase of weight gain which lasted 10 weeks, a linear phase of fattening continued for an additional 30 weeks at a rate approximately double that of operated control rats of the same age. During this second phase of fattening, lesioned rats were food-restricted between the 20th and 26th weeks postlesion. Compared to the rate of weight gain in the linear phase prior to food restriction, the rate over the same weight range following release from food restriction was significantly greater for both DC and RF-lesioned rats. Furthermore, by the 40th postlesion week, the lesioned rats had approached the weight they would have been if not food restricted. These observations suggest that VMH area lesions induce a gradual climbing of the set-point for body weight which occurs independently of actual food intake or body weight, and which either follows or is superimposed on the immediate elevation of the set-point responsible for the initial, curvilinear phase of weight gain. As a model for human idiopathic obesity, the long-term effect of VMH area lesions may be more important than the immediate effect.