sfn2004

Conner JM, Chiba AA, Tuszynski MH (2004) The basal forebrain cholinergic system is essential for cortical plasticity and functional recovery following brain injury. Neuroscience 2004 Abstracts 685.12. Society for Neuroscience, San Diego, CA.

Summary: Localized damage to the motor cortex typically results in impaired motor function. Functional recovery following focal brain injury presumably requires the reorganization of cortical circuitry, enabling undamaged areas remote from the lesion site to take over function. Neuronal mechanisms mediating plasticity of cortical representations are not fully understood, but recent studies have indicated that the basal forebrain cholinergic system may play an essential role. In the present study, we investigated the hypothesis that the basal forebrain cholinergic system is essential for enabling cortical reorganization required for functional recovery following focal motor cortex lesions. Following focal cortical injury, performance in a previously learned skilled reaching task dropped by ~75%. After 5-weeks of rehabilitative training, normal (cholinergically-intact) rats recovered 55.2 ± 4.4% of their pre-lesion reaching performance. Rats with specific lesions of the cholinergic neurons projecting to the cortex showed only 18.1 ± 7.7% recovery (p<0.002). Intracortical mapping revealed that massive reorganization of motor representations had occurred in the cortex following focal cortical injury and rehabilitative training. A significant 48.6 ± 12.2% increase (p=0.001) in the size of the rostral forelimb area (RFA) was seen in cholinergically-intact, functionally recovered, rats. In contrast, the size of the RFA did not change in cholinergic-lesioned animals. Subsequent ablation of the RFA completely disrupted skilled reaching performance, suggesting the RFA was essential to the recovered function. These results demonstrate that functional recovery following discrete cortical injury requires basal forebrain cholinergic mechanisms and suggest that the basis for this recovery is the cholinergic-dependent reorganization of motor representations.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Tait DS, Brown VJ (2004) Cell-body lesions of basal forebrain impair reversal learning but not attentional set-shifting in rats. Neuroscience 2004 Abstracts 779.12. Society for Neuroscience, San Diego, CA.

Summary: There is considerable evidence for a role of basal forebrain acetylcholine in a wide range of attentional tasks (see Sarter & Bruno, 2000, Neurosci, 95:933-952), but previous work from this laboratory found that basal forebrain cholinergic projections are not critical for the acquisition, maintenance and shifting of attentional set (Tait et al, 2002 SfN abstr 286.2). As GABAergic basal forebrain projections to cortex may be important for “cognitive flexibility” (Sarter & Bruno, 2002, Eur J Nsci, 15:1867-1873), the present study assessed the effects of non-specific basal forebrain lesions. Male Lister hooded rats received infusions of 200nl 0.06M ibotenic acid into basal forebrain, at coordinates: nosebar –3.3; AP –0.9; ML ±2.9; DV –6.9. We used the rat attentional-set shifting task (Birrell & Brown, 2000, JNsci, 20:4320-4324), in which rats forage in digging bowls for food rewards, to assess discrimination learning (based on the odor of the bowls or the medium in which the food was hidden), reversal learning and attentional-set shifting (when the relevant aspect of the stimulus is switched; for example, a rat previously attending to odor, now must attend to digging medium or vice versa). There was no impairment in discrimination acquisition or in shifting of attentional-set. Lesioned rats were impaired only on the first of three discrimination reversals, taking significantly longer to reach criterion than controls. Prior evidence indicating no effect of selective BF cholinergic depletion via 192-IgG-saporin administration on reversal performance (Tait et al, 2002) leads us to conclude that the non-cholinergic neurons – most likely the GABAergic projection to prefrontal cortex and thalamus – have an important role in reversal learning. These data are strikingly similar to the effects of excitotoxic basal forebrain lesions in monkeys (Roberts et al, 1992, NSci, 472:251-264).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Cordova CA, Yu AJ, Chiba AA (2004) Attention, uncertainty, and acetylcholine: Effects of nucleus basalis cholinergic lesions on probabilistic inference. Neuroscience 2004 Abstracts 779.13. Society for Neuroscience, San Diego, CA.

Summary: Animal investigations suggest that the basal forebrain corticopetal cholinergic system helps to regulate attention to unpredictable events. In light of these findings, computational theorists propose that cholinergic neurons precisely alter the way that sensory stimuli are processed in the cortex in light of how well predicted they are. In an initial test of this theory, two groups of rats were trained to respond to probabilistic stimuli presented serially in one of four spatial locations with varying degrees of predictive uncertainty (arising from a 2-layer Hidden Markov model). Following training, one group of rats was given a selective cholinergic lesion of the nucleus basalis/substantia innominata region of the basal forebrain using 192-IgG Saporin. The lesioned rats were unable to allocate attention appropriately, as evidenced by the decreased accuracy of responses to less probable stimuli. These findings provide support for the notion that the basal forebrain corticoptetal cholinergic system facilitates attention by regulating the balance of learned expectations and sensory processing during stimulus inference.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Taylor CL, Rostron PR, Latimer MP, Winn P (2004) Behavioral characteristics of pedunculopontine tegmental nucleus lesioned and nucleus basalis magnocellularis lesioned rats in a test of vigilance. Neuroscience 2004 Abstracts 780.4. Society for Neuroscience, San Diego, CA.

Summary: Previous work has shown pedunculopontine tegmental nucleus (PPTg) lesioned rats make more omissions on a vigilance task but improve if the target is longer. We compared vigilance performance of PPTg rats with rats bearing 192 IgG Saporin lesions of the nucleus basalis magnocellularis (NbM). The task involved a period of darkness before a dim light of variable duration, followed by a bright light target. A lever press was required during the target to receive food reward, while failure to press during the target constituted an omission. Rats were pre-trained to a criterion of >70% correct and <20% omissions at 1500ms target duration. Post-lesion, rats were assessed for 10 days at 1500ms, 5 days at 4000ms, and 5 further days at 1500ms target durations. Results showed both groups increased omissions relative to controls but this effect was transient in NbM rats. The percentage of omissions in all groups was sensitive to manipulation of target duration. Because increasing target duration also increased the time allowed to make a correct response we re-coded omissions in the 1500ms task to include only those occurring a further 2500ms following target offset (making the response time frame comparable with the 4000ms task). Again, comparison with omissions from the 4000ms task continued to show target duration sensitivity. This finding lends support to PPTg as well as NbM involvement in attention. In order to address why lesioned rats made more omissions in the task we analyzed video data of behaviour at the time of the dim and bright light. Results suggest increased distraction in PPTg lesioned rats while NbM lesioned rats additionally showed failed attempts to lever press in response to the bright signal. This finding has implications for studies using short response time frames where NbM rats may not have time to recover from a failed lever press attempt.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Truitt WA, Dietrich AD, Fitz SD, Minick PE, Shekhar A (2004) Neurokinin 1 receptor expressing interneurons of the BLA regulate anxiety-like responses in the rat. Neuroscience 2004 Abstracts 782.5. Society for Neuroscience, San Diego, CA.

Summary: The Basolateral Nucleus of the Amygdala (BLA) has been implicated in the regulation and development of anxiety. In general, regarding BLA projection neurons, excitation tends to increase, while inhibition tends to reduce anxiety-like responses. These projection neurons, which comprise approximately 85% of the BLA neurons, are tightly regulated by the activity of local circuit GABAergic interneurons. To date, at least four distinct interneuronal subpopulations have been identified in the BLA, with characteristic morphological and physiological properties suggestive of functional diversity. Yet the in vivo functional selectivity of these subpopulations has not been critically examined. Here we propose to examine the function of one specific interneuronal subpopulation within the BLA by making selective lesions and monitoring anxiety-like behavior. To accomplish this objective the subpopulation of BLA interneurons expressing NK-1r receptors were ablated with the targeted toxin SSP-saporin (SAP). Lesions were made by a series of 6 bilateral, 500nl injections spread throughout the anterior BLA. Control rats were injected with an equal volume of blank-SAP, which does not enter the cells. SSP-SAP injections significantly reduced the number of NK-1r expressing cells compared to blank-SAP treated rats, with little to no nonspecific damage. Lesioning NK-1r expressing cells resulted in increased anxiety-like responses in the social interaction (SI) and elevated plus maze (EPM) tests. Specifically, SI time compared to pre-surgery value was significantly reduced in lesion rats. Lesion rats also had fewer open arm entries in the EPM compared to control rats. Furthermore, lesioned rats failed to recover from this decrease in SI even after 4 weeks of testing. These results suggest that the subpopulation of interneurons within the BLA that express NK-1r is critical in regulating anxiety-like behavior.

Related Products: SSP-SAP (Cat. #IT-11)

Stead S, Doering LC (2004) A novel mouse model for Parkinson’s disease using an immunotoxin directed at the dopamine transporter. Neuroscience 2004 Abstracts 563.1. Society for Neuroscience, San Diego, CA.

Summary: Current laboratory models of Parkinson’s disease utilize neurotoxins directed at midbrain dopamine neurons to mimic nigro-striatal dopaminergic neuron degeneration. To date, however, there is no single model that accurately simulates the pathogenic, histological, biochemical and clinical features relevant for the investigation of PD. The most common laboratory rodent model of Parkinson’s uses the neurotoxin 6-hydroxydopamine (6-OHDA) to cause relatively acute degeneration of the dopamine neurons in the substantia nigra (Schwarting RKW and Huston JP, 1996, Prog Neurobiol., 50:275-331). Axonally transported toxins can be used to make selective lesions in the central nervous system. We have found that a slower degeneration of the SN can be achieved with an immunotoxin directed against the dopamine transporter (DAT). This immunotoxin, consisting of the highly active ribosome inactivating protein Saporin linked to an antibody to the dopamine transporter, was recently reported to cause selective degeneration of the SN in rats (Wiley RG et al., 2003, Cell Mol Neurobiol., 23:839-850.). We have shown that unilateral stereotaxic injection of the Anti-DAT-Saporin into the striatum of female C57BL6 mice causes a progressive reduction in the numbers of DA neurons in the SN in comparison to the non-lesioned hemisphere, and sham controls. Furthermore, in parallel to the immunohistochemical dopamine neuron death, the animals display a pronounced circling behaviour when challenged with apomorphine (6mg/kg). This model is akin to the gradual deterioration of the nigro-striatal system that occurs in Parkinson’s Disease and provides a system to intervene at various stages of dopamine neuron loss and evaluate the effectiveness of stem cell therapy.

Related Products: Anti-DAT-SAP (Cat. #IT-25)

Leung LS, Petropoulos S, Ma J, Shen B (2004) Cholinergic neurons in the basal forebrain participate in consciousness and general anesthesia. Neuroscience 2004 Abstracts 565.4. Society for Neuroscience, San Diego, CA.

Summary: Acetylcholine (Ach) in the brain has long been associated with consciousness. In this study, we assessed consciousness in rats by their EEG and behavioral responses to a general anesthetic. Cholinergic neurons in the nucleus basalis of Meynert (NbM) were lesioned by bilateral injection of toxin IgG192-saporin (0.15 μg at P1.4, L2.7, 7.7 mm below dura) in 10 adult male rats. Control (5 rats) had saline injected into the NbM. EEGs were recorded by electrodes placed in layer V of the frontal cortex (FC) and visual cortex (VC). Spectral analysis of the spontaneous EEGs in FC and VC during awake-immobility indicated that lesioned animals showed higher delta (0.8 to 4 Hz) and lower gamma (30- 58 Hz) power as compared to controls. Subsequent acetylcholinesterase staining (optical density) confirmed significant Ach depletion in both FC and VC, in the lesion as compared to the control group (P<0.002, Wilcoxon). When challenged with a normally subanesthetic dose of general anesthetic, the lesioned rats showed, as compared to controls, significantly longer durations of loss of righting and tail-pinch response after 5 mg/kg i.v. propofol (P<0.001), but not after 20 mg/kg i.p. pentobarbital or 2% halothane. In correspondence with the deep behavioral anesthesia, delta power at FC after propofol was significantly larger in lesioned than control rats. Lesioned rats, as compared to controls, also showed decreased locomotion (behavioral excitation) when given 2% halothane in a large chamber. In summary, a loss of Ach in the neocortex decreases the level of consciousness as indicated by increased delta and decreased gamma EEG, and by an increased sedative/ anesthetic response to propofol i.v. We suggest that patients with Alzheimer disease may show altered response to some general anesthetics.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Ohara PT (2004) Exercise accelerates relapsing paralysis after recovery from spinal demyelination. Neuroscience 2004 Abstracts 419.6. Society for Neuroscience, San Diego, CA.

Summary: Exercise has been used to improve motor performance in humans and animals following spinal cord injury. The effects of exercise are generally positive but it is not known whether exercise is universally beneficial, particularly in rat models of spinal injury. We examined the spinal cord morphology and motor function recovery for 18 months in rats that had undergone lumbar spinal demyelination induced by CTB-saporin. Following the initial demyelination and paraplegia, motor function recovered and was stable for up to nine months after which there occurred a slow deterioration of function that occurred earlier and was more severe in rats that had been exercised on a treadmill. Rats given treadmill exercise starting three weeks after toxin injection had a mean motor deficit score of 3.0 (i.e. paraplegia) at perfusion while the non-treadmill treated rats had a mean score of 1.8 (SD 0.38, n = 6, p<0.05). Histological examination showed the same morphological changes occurred in both exercise and non-exercise treated animals including the loss of motoneurons, loss of spinal white matter and appearance of large spheroids of calcium in the ventral and dorsal horns and occasionally in the white matter. These findings suggest that, in addition to the acute effects of the toxin induced demyelination from which there is recovery of motor function, there are chronic irreversible effects of the toxin, or the initial demyelination, that cause a slow progressive degeneration of the spinal cord. This model might therefore be useful to study the long term effects of spinal insult of the type associated with conditions such as post-polio syndrome.

Related Products: CTB-SAP (Cat. #IT-14)

Janczewski WA, McKay LC, Feldman JL (2004) Decreased number of sighs and post-sigh apneas indicates neuronal degeneration within the preBötzinger complex. Neuroscience 2004 Abstracts 424.10. Society for Neuroscience, San Diego, CA.

Summary: Sighs, also known as augmented or deep breaths, are inspiratory efforts of increased tidal volume, duration and biphasic shape. Sighs occur periodically in most mammals and are present throughout life, even in utero. Some sighs are followed by a post-sigh apnea lasting longer than 2 average respiratory periods. In adult rats, the number of sighs per hour [sigh index (SI)] is ~20. When we injected 0.2 pmol of substance P (SP) into the preBötzinger Complex, SI increased to >100, suggesting that activation of preBötzinger Complex NK1 receptor expressing (NK1R) neurons produces sighs. We hypothesized that degeneration of preBötzinger Complex NK1R neurons would decrease SI and eliminate post-sigh apneas. We injected the toxin saporin conjugated to SP bilaterally into the preBötzinger Complex to selectively destroy NK1R neurons. The number of ablated NK1R neurons increased from days 2-6 postinjection. In all rats at days 2-3, SI dropped below 5 and all post-sigh apneas were eliminated. In one group of rats (n=6), an ataxic breathing pattern developed, resulting from >90% NK1R cell loss. In these rats, all sighs were eliminated from days 3-4 postinjection. A second group of rats (n=5) maintained a eupneic breathing pattern. They were observed for two months postinjection and did not recover the preinjection sigh pattern. Their NK1R cell loss was <80% after two months, but must have been smaller at day 2 postinjection when their sigh pattern changed. We hypothesize that a modest (<< 80%) decrease in the number of NK1R neurons within the preBötzinger Complex, due to a toxin here but otherwise due to aging or neurodegenerative processes, may explain the decrease in SI seen with age in humans. We postulate that a marked decrease in the number of sighs and post-sigh apneas is an early symptom of neurodegeneration within the preBötzinger Complex.

Related Products: SP-SAP (Cat. #IT-07)

McKay LC, Janczewski WA, Feldman JL (2004) Ablation of NK1 receptor-expressing (NK1R) neurons within the preBötzinger complex (preBötC) in adult rats disrupts breathing during sleep before affecting breathing in wakefulness. Neuroscience 2004 Abstracts 424.9. Society for Neuroscience, San Diego, CA.

Summary: In adult rats, as the number of ablated preBÖtC NK1R neurons increases, eupnea is progressively disrupted during wakefulness, eventually resulting in an ataxic breathing pattern when cell loss is >80% (Gray et al. Nat. Neurosci. 2001). Is there a disruption of breathing during sleep prior to a disruption of breathing in wakefulness? Adult male Sprague Dawley rats (n=4) were instrumented to record: diaphragmatic, abdominal and neck EMG; ECG, and; EEG. Subsequently, the toxin Saporin conjugated to Substance P was injected bilaterally into the preBÖtC to selectively destroy NK1R neurons. Rats were monitored from day 1 postinjection until they were sacrificed between days 9-15. On days 3-4, changes in breathing pattern were observed during REM sleep. These changes were characterized by an increase in frequency of central apneas (4-7/hour vs 2/hour preinjection controls; p<0.05) and an increase in apnea length (3-6 sec vs 1-2 sec preinjection controls; p<0.05). On days 4-6, the onset of REM sleep typically induced hypopnea and a central apnea resulting in an arousal to wakefulness within 4-10 sec and the reestablishment of a normal breathing pattern. Eupnea was maintained during wakefulness; in some cases there was an increase in frequency compared to preinjection controls (183 vs 120 breaths/min). From day 6 onwards, breathing rhythm was progressively disrupted until an ataxic breathing pattern developed during wakefulness (~day 8). At this stage, rats were unable to sleep because breathing stopped upon sleep onset. In all cases, lesion extent at sacrifice, as determined by histology, was confined to the preBÖtC and >80% of NK1R neurons were destroyed. The spreading ablation of preBÖtC NK1R neurons results in a progressive disruption in breathing pattern, initially during sleep leading to pathological disturbances of breathing in both sleep and wakefulness.

Related Products: SP-SAP (Cat. #IT-07)