sfn2004

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.

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Ritter S, Flynn FW, Dinh TT (2004) Immunotoxic destruction of hindbrain catecholamine neurons impairs the vasopressin response to hypovolemia. Neuroscience 2004 Abstracts 660.4. Society for Neuroscience, San Diego, CA.

Summary: In order to better understand the involvement of hindbrain catecholamine neurons in hypovolemia-induced vasopressin secretion, we lesioned these neurons selectively using anti-dopamine beta-hydroxylase (dbh) conjugated to the ribosomal toxin, saporin (DSAP). When injected into catecholamine terminal sites, this neurotoxin is selectively internalized by and retrogradely transported in dbh-containing neurons, destroying cell bodies that innervate the injection site. We microinjected DSAP or unconjugated saporin (SAP) control bilaterally into the medial hypothalamus of female rats to destroy catecholamine neurons innervating the magnocellular areas of the paraventricular nucleus (PVH). The lesion was verified at the conclusion of the experiment by analysis of dbh-immunoreactive terminals in the PVH and cell bodies in hindbrain catecholamine cell groups. Two weeks after DSAP injection, hypovolemia was induced by remote withdrawal of blood (1 ml/min for 4.5 min) using a chronically implanted intra-atrial catheter. Blood was sampled between 0-2 and 2-4.5 min and at 20 and 50 min after the start of blood withdrawal. Plasma vasopressin was extracted and analyzed using ELISA. The DSAP lesion severely impaired the vasopressin response. Responses at 20 min were 35 pg/ml in the SAP control and 21 pg/ml in the DSAP rats. Responses at 50 min were 45 pg/ml in the SAP and 23 pg/ml in the DSAP lesioned rats. Results indicate that hindbrain catecholamine neurons play a crucial role in full expression of the vasopressin response to hypovolemia.

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Xu F, Zhuang J, Hernandez J, Shi S (2004) Apnea induced by stimulation of bronchopulmonary C-fibers (PCFs) depends on neurons expressing the neurokinin a receptor (NK1R) in the commissural subnucleus of the nucleus tractus solitarius (cNTS). Neuroscience 2004 Abstracts 661.13. Society for Neuroscience, San Diego, CA.

Summary: Stimulation of PCFs by right atrial injection of capsaicin (CAP) reflexly produces an apnea and hypotension via stimulating cNTS neurons. Recent evidence indicates that activation of NK1R within the cNTS significantly amplifies this apneic response (Mutoh, et al., Am J Physiol, 2000). We asked whether the cNTS contained the highest density of the neurons responding to PCF stimulation and expressing NK1R, and what the effect of selective destruction of these neurons was on the cardiorespiratory responses to CAP. In the first series of our experiments, double labeling (c-fos and NK1R immunoreactivity) was used to mark the medullary neurons that were activated by right atrial injection of CAP (0.5-1.0 µg) and displayed NK1R. We found that compared to control (vehicle injection), the greatest enhancement of and highest density of Fos expression were observed within the cNTS, and a number of Fos-stained cNTS neurons had expression of NK1R. In the second series of our experiments, bilateral microinjection (100 nl) of substance P-saporin conjugate (SP-SAP) to selectively destroy the local neurons containing NK1R and SAP (control) into the cNTS was performed in two groups of rats, respectively. Our results showed that at 18 days after SP-SAP (rather than SAP) injection, the majority of cNTS NK1R neurons were destroyed. This lesion did not significantly change cardiorespiratory baseline variables, but did eliminate the apnea and reduce the hypotension induced by CAP. In sharp contrast, the lesion failed to affect the cardiorespiratory responses to hypoxia (10% O2 for 1 min). These findings strongly suggest that cNTS neurons with NK1R are necessary for the PCF-mediated cardiorespiratory responses but are not significantly involved in the cardiorespiratory response to acute hypoxia.

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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.

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Banihashemi L, Rinaman L (2004) Noradrenergic inputs to the bed nucleus of the stria terminalis (BNST) contribute to yohimbine-induced activation of BNST neurons and hypothalamic CRH neurons in rats. Neuroscience 2004 Abstracts 426.10. Society for Neuroscience, San Diego, CA.

Summary: Noradrenergic (NA) inputs to the BNST and hypothalamus are implicated in behavioral and endocrine responses to stress and anxiety. Yohimbine (YO) increases transmitter release from NA terminals, which promotes anxiety and activates CRH neurons at the central apex of the HPA axis. We hypothesized that these effects require NA signaling within the BNST. To test this, saporin toxin conjugated to an antibody against dopamine beta hydroxylase (DSAP; 50-100 nl) was microinjected bilaterally into the BNST to eliminate its NA inputs in adult male Sprague-Dawley rats. After 2 weeks, DSAP-treated rats and intact control rats were injected with YO (0 or 5 mg/kg, i.p) and perfused with fixative 90 min later. Brain sections were processed to reveal DSAP lesion extent and YO-induced cFos activation. DSAP rats displayed nearly complete loss of NA terminals in the BNST, accompanied by moderate loss of hypothalamic NA terminals. Significantly fewer BNST neurons and hypothalamic CRH neurons were activated in DSAP rats after YO compared to activation in intact control rats, whereas parabrachial and central amygdala activation in DSAP rats was not diminished. We conclude that medullary NA neurons projecting to the lateral BNST collateralize to innervate the paraventricular hypothalamus, and that these NA projection neurons are necessary for YO to activate BNST and hypothalamic CRH neurons. Studies are ongoing to determine whether BNST-projecting NA neurons are necessary for YO to inhibit food intake or support conditioned flavor avoidance.

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Pizzo DP, Samadzadeh L, Thal LJ, Frielingsdorf H (2004) Impact of 192 IgG-saporin medial septum lesions on working memory. Neuroscience 2004 Abstracts 436.1. Society for Neuroscience, San Diego, CA.

Summary: It is generally believed that cholinergic input to the hippocampus (hpc) is involved in learning and memory. The objective of the present study was to clarify whether working memory as assessed by the Morris water maze (mwm) is impaired by selective lesions of the cholinergic cells in the medial septum in adult male rats using 75 ng192IgG-saporin per side. Two weeks post-lesion, naive and lesioned rats were trained in the mwm task focusing on working memory, which was tested using a new platform location every day. The difference (improvement) in latency between trial 1 and 2 was used as an index of working memory function. Nine different platform locations were tested. The locations yielding the highest group difference were retested, with increasing intertrial intervals (ITI) from 30 min to 24 h between the 1st and 2nd trial. In a majority of the trial blocks there was a trend suggesting that lesioned rats had impaired working memory, however there was no consistent significant difference between groups in any of the tasks. To potentially further separate the groups rats were then infused with nerve growth factor (NGF; 5 µg/day), or vehicle into the ventricular system. After 17 days of infusion working memory was retested, however NGF treatment did not affect performance. The lesions were complete as measured by loss of choline acetyltransferase activity (ChAT) to less than 10% of levels of the naive, vehicle treated rats. NGF infusion increased hpc ChAT activity in naive but not in lesioned rats. In conclusion, selectively reducing ChAT activity by more than 90% in the hpc is not sufficient to significantly impair working memory as assessed by the mwm. We cannot exclude that a more sensitive working memory task would reveal a deficit in the lesioned animals, however it is also possible that intact septohippocampal cholinergic projections are not crucial for working memory function.

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

Corley SR, Atkinson M, Cabrera S, Castillo A, Crawford D, Kitto M, Butt AE (2004) Cholinergic basal forebrain lesions disrupt acquisition of cued and uncued differential reinforcement of low rate responding. Neuroscience 2004 Abstracts 436.10. Society for Neuroscience, San Diego, CA.

Summary: The frontal cortex, medial septum/vertical diagonal band (MS/VDB), and hippocampus have been implicated in supporting differential reinforcement of low rate responding (DRL) behavior in rats. Because the frontal cortex and hippocampus receive cholinergic input from the basal forebrain, we hypothesized that 192 IgG-saporin (SAP) lesions of the basal forebrain would disrupt DRL acquisition in the current experiment. To distinguish between potential deficits in timing, as opposed to impairments in response inhibition, we trained rats in either the standard DRL task (which requires both timing of behavior and response inhibition) and on a cued version of the task (which does not require the ability to time behavior but does require response inhibition). Rats were first shaped to bar press before receiving either bilateral SAP lesions of the basal forebrain or sham lesions. Rats were returned to bar press training for 5 more days. Rats were then shifted to a DRL 20 s, LH 10 s (limited-hold 10 s) schedule of reinforcement. Half of the rats were provided with a cue light signaling the availability of reinforcement, whereas the other half underwent standard DRL 20 s LH 10 s testing without the visual cue. Rats with basal forebrain lesions showed a transient impairment in response inhibition in both the standard and the cued version of the DRL task. Both lesion groups made more responses at short inter-response-intervals than controls across the first 15 test days, although this impairment attenuated by the 20th test day. These data suggest that the cholinergic basal forebrain is involved in learning to withhold responding during acquisition in DRL.

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Arshad S, Li P, Fitz NF, Johnson DA (2004) Effect of dehydroepiandrosterone sulfate on retention in passive avoidance in septal hippocampal cholinergic lesioned rats. Neuroscience 2004 Abstracts 436.11. Society for Neuroscience, San Diego, CA.

Summary: Infusions of 192 IgG-saporin (SAP) into the medial septum (MS) selectively destroys cholinergic neurons projecting to the hippocampus. Our previous study demonstrated that this lesion impairs retention but not acquisition of a passive avoidance (PA) task in rats. The present study determined whether the neurosteroid Dehydroepiandrosterone sulfate (DHEAS) (0, 1, 3, 10, 30 mg/ml) could reverse SAP induced impairments of PA retention. Male Sprague-Dawley rats were administered either SAP (.22μg/μl) or vehicle directly into the MS. Passive Avoidance training began 2 weeks later. Training consisted of placing the animal into the lighted chamber of the apparatus and then delivering a foot shock (.75mA, 1 sec), when the animal moved into the adjacent darkened chamber. Training was repeated until the animal avoided the dark chamber for 2 consecutive trials of 2 minutes duration. Retention (latency to crossover to the dark chamber) was tested after seven days. DHEAS was administered one hour prior to retention testing. Results showed a dose dependent increase in crossover latency in SAP treated animals. DHEAS treatment in control animals, however, resulted in a dose dependent decrease in crossover latency. Thus, DHEAS attenuated the impairment in retention in SAP treated animals with hippocampal cholinergic hypofunction, but impaired retention in cholinergically intact rats in PA.

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