sfn2007

Gompf HS, Fuller PM, Saper CB, Lu J (2007) Locus coeruleus (LC) is involved in sustaining arousal. Neuroscience 2007 Abstracts 736.3/UU16. Society for Neuroscience, San Diego, CA.

Summary: The locus coeruleus (LC) has traditionally been thought to be involved in arousal; however, lesions of the LC have minimal effects on basal sleep-wake behavior. We propose that the LC instead may be required to sustain arousal under conditions of environmental challenge. To test this hypothesis, we intraventricularly injected saline, or 0.25, 0.5, or 1µg anti-DBH-saporin (DBH-SAP selectively lesions the LC), and implanted EEG/EMG electrodes. On recording days, each animal was paired with a normal rat (social interaction) and presented with novel objects every hour for 5 hours from ZT 6 to ZT 11. We then repeated the same experiment for 2.5 hrs and immunostained tissue for Fos and TH or Fos and DBH. We also repeated the same experiment in rats with unilateral LC lesion by 6-OHDA. During 5 hr of stimulation with novel objects and social interaction (distracting stimuli, DS), controls or partial LC lesioned animals (0.25 µg DBH-SAP) spent 83 ± 8% and 92 ± 4% awake respectively (n = 3 and 4, p = 0.4) whereas animals with complete LC lesions (0.5 and 1 µg) spent significantly less time in wakefulness (59 ± 4% and 66 ± 5% respectively, n = 3 and 4, p = 0.0005). The reduction of wakefulness occurred primarily during the second 30 mins of each hour. Following DS exposure, Fos was highly expressed in the cerebral cortex in both LC lesioned groups and controls. Furthermore, we found a correlation (R2 = 0.79) between the remaining LC neurons and wakefulness under DS. Rats with loss of one LC showed no changes in wakefulness, and Fos was highly and symmetrically induced in the cerebral cortex. Our results suggest that the LC is specifically involved in sustaining arousal.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Martin MM, Carter LA, Jones JL, Winter SS, Wallace DG (2007) Organization of food protection behavior is differentially influenced by hippocampal and cortical cholinergic deafferentation. Neuroscience 2007 Abstracts 742.6/AAA9. Society for Neuroscience, San Diego, CA.

Summary: Previous work has suggested that rats use temporal information to organize their food protection behaviors. Studies have demonstrated different roles for hippocampal and cortical cholinergic function in processing of temporal information in standard interval timing procedures. The present study examined the role of hippocampal and cortical cholinergic function on the organization of food protection behavior. Long Evans female rats received either injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum (MS) or nucleus basalis (NB). Subsequent to recovery, rats were placed into an enclosure and provided a hazelnut in the presence of an unoperated conspecific. All rats engaged in dodging or bracing behaviors to prevent the theft of the hazelnut. During a dodge, the rat places the food item in its mouth to use both fore- and hind-limbs to escape the approaching conspecific. In contrast, during a brace, the rat’s forelimbs maintain contact with the food item, and only the hind limbs are used to make shorter lateral movements. Only rats receiving sham lesions displayed a consistent transition from primarily engaging in dodging behavior to primarily engaging in bracing behavior during the consumption of the hazelnut. The MS SAP group displayed a disruption in their temporal organization of food protection behaviors. Although the NB SAP animals displayed impaired responding to the approaching conspecific (resulting in frequent thefts), their food protection behaviors tended to exhibit temporal organization. These results provide further evidence as to the role of the basal forebrain cholinergic system in temporal organization of behavior.

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

Wallace DG, Knapp SK, Silver JA, Martin MM, Winter SS (2007) Selective hippocampal cholinergic deafferentation disrupts exploratory trip organization. Neuroscience 2007 Abstracts 743.17/BBB11. Society for Neuroscience, San Diego, CA.

Summary: Rats organize their exploration of an environment around a central location or home base. Movements away from the home base are characterized as a series of slow progressions punctuated by stops. Subsequent to the last stop, the homeward segment is a single, rapid progression associated with a consistent temporal pacing of linear speeds. Observing these characteristics of exploratory behavior independent of environmental cue availability or familiarity has supported rats’ use of self-movement cues generated after departing the home base to estimate the distance and direction back to the home base. The current study investigated the effects of selective hippocampal cholinergic deafferentation on home base establishment and exploratory trip organization. Long Evans female rats either received injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum. Subsequent to recovery, rats were placed on a large circular table with access to a refuge under complete dark conditions (infrared cameras and goggles were used to visualize the rat). Although all rats established a home base in the refuge, impairments in exploratory trip organization specific to the homeward segment were observed in SAP rats. Specifically, SAP rats displayed inconsistent temporal pacing of homeward segment linear speeds. These observations are consistent with a role for hippocampal cholinergic function in processing self-movement cues.

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

Young D, Howe WM, Martinez V, Bruno JP, Sarter M (2007) Neuronal mechanisms underlying the cognitive symptoms in a model of schizophrenia: prefrontal cholinergic inputs are necessary for attentional performance following repeated exposure to amphetamine. Neuroscience 2007 Abstracts 606.9/GG1. Society for Neuroscience, San Diego, CA.

Summary: The neuronal and cognitive effects of repeated exposure to amphetamine (AMPH) model important aspects of schizophrenia. Our prior results indicated that the attentional performance of AMPH-pretreated animals was maintained by abnormally high levels of prefrontal acetylcholine (ACh) release, and that the disruption of attentional performance by AMPH challenges was associated with a failure of the prefrontal cholinergic input system to respond to task onset (Kozak et al. 2007). The present experiment was designed to demonstrate that prefrontal cholinergic inputs are necessary for the (residual) attentional performance following repeated AMPH exposure. As removal of cortical cholinergic inputs per se disrupts attentional performance, we tested the hypothesis that limited prefrontal cholinergic deafferentation, which does not affect baseline attentional performance, prevents the establishment of normal performance following AMPH pretreatment. Rats were trained to perform a sustained attention task requiring the detection of visual signals and the discrimination between signal and non-signal events. Bilateral infusions of small concentrations and volumes of the immunotoxin 192 IgG-saporin into the medial prefrontal cortex did not affect the animals’ baseline performance. After re-establishing stable baseline performance, animals were pretreated with either saline or AMPH in accordance with an established, non-neurotoxic, escalating dosing regimen (1-10 mg/kg, twice daily over 40 days; Robinson et al. 1988). Animals were tested daily throughout the experiment. Following completion of the pretreatment regimen, the attentional performance of sham-lesioned controls recovered slowly over three weeks of continued training/testing. In contrast, performance recovery of deafferented, AMPH-pretreated animals was robustly attenuated and failed to reach pre-treatment levels. Collectively, these results indicate the necessary role of the prefrontal cholinergic input system in mediating the residual attentional performance of repeated AMPH. Therefore, pro-cholinergic treatments are predicted to benefit the attentional performance of schizophrenics. Repeated AMPH serves as a useful model to investigate the neuronal mechanisms underlying the cognitive symptoms of schizophrenia.

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

Ganapini V, Powers F, Kuper K, Taylor A, Fraley GS (2007) Galanin-like peptide stimulates feeding and sexual behavior via dopaminergic fibers within the medial preoptic area of adult male rats. Neuroscience 2007 Abstracts 626.14/VV17. Society for Neuroscience, San Diego, CA.

Summary: Galanin-like peptide (GALP) is a hypothalamic neuropeptide known to regulate both food intake and sexual behaviors in adult male rats. We have demonstrated that ICV GALP administration elicits a significant fos response within the mPOA; thus, we feel that GALP stimulates feeding and reproduction by actions within the mPOA. Recent data from our and other labs have led us to suspect that GALP effects on these behaviors are due to activation of tuberoinfundibular dopaminergic neurons that terminate within the mPOA. To test the hypothesis that GALP activates mPOA dopaminergic systems, we utilized an immunolesion technique to eliminate dopaminergic fiber input specific to the mPOA via a dopamine-transporter specific toxin (DATSAP, n = 8) and compared to control injections (SAP, n = 8). All animals were sexually experienced adult male Long Evans rats. We first tested their response to a sexually-primed female rat. DATSAP-treated male rats showed a significant (p <0.001) reduction in male sexual behavior compared to SAP controls. We found that elimination of dopamine fibers within the mPOA significantly (p < 0.001) eliminated all aspects of male sexual behavior under normal mating paradigms. Injections of GALP (5.0 nmol) significantly increased (p < 0.01) male sex behavior in SAP control male rats but GALP was unable to stimulate the expression of these behaviors in DATSAP-treated rats. ICV GALP significantly (p < 0.05) stimulated fos within the mPOA of SAP rats but not in DATSAP-treated male rats. There was no significant difference in 24 hr food intake between SAP and DATSAP rats. However, the orexigenic effect of ICV GALP was significantly (p < 0.001) attenuated in DATSAP-treated male rats compared to SAP controls. These data suggest that GALP activates feeding and sexual behaviors in male rats by stimulating dopaminergic neurons that terminate within the mPOA.

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I’Anson H, Jethwa PH, Tanna GA, Pattinson LM, Ebling FJP (2007) Histaminergic regulation of energy homeostasis in the Siberian hamster. Neuroscience 2007 Abstracts 629.17/YY20. Society for Neuroscience, San Diego, CA.

Summary: We tested the hypothesis that posterior hypothalamic histaminergic (HA) activity regulates energy homeostasis in the Siberian hamster during long day (breeding season) photoperiods. Adult male Siberian hamsters were given bilateral injections of the retrogradely transported ribosomal toxin, saporin, conjugated to orexin-B receptor antibody (OXSAP, 200 nl, 92 ng/ul) into the posterior hypothalamus (PH) to selectively destroy HA neurons, the majority of which possess orexin-B receptors. Controls were injected with unconjugated saporin (sham). Metabolic rate (VO2 ml/kg0.75/h), ingestive behavior and locomotor activity were monitored using the comprehensive lab animal monitoring system (CLAMS, Columbus instruments). Body weight was significantly decreased by day 12 post-surgery in OXSAP compared with sham hamsters and remained significantly lower throughout the 5 month study, even though food intake was comparable between groups. At 3 months post-surgery, OXSAP food intake was significantly higher in the dark (p< 0.05) and significantly lower in the light phase (p<0.05), but not different overall between groups. In addition, the frequency of feeding bout tended to be lower during dark and light phases compared with sham hamsters (p=0.07). Lower body weight with no overall change in food intake suggests an increase in energy expenditure in the OXSAP hamsters. Consistent with this interpretation, locomotor activity in OXSAP hamsters tended to be higher during the dark phase (p=0.09), but not in the light phase. In addition, metabolic rate was significantly higher during the first two hours of the dark phase compared with sham hamsters (p<0.05), and tended to be higher during the entire dark phase (p=0.08). During a second CLAMS study (4 months post-surgery), metabolic rate was monitored following injection of an H3 receptor antagonist (thioperamide, 30 mg/kg, ip) as a probe to determine if any significant HA cell loss had occurred. Metabolic rate was significantly lower during the first 2 hours after thioperamide in sham hamsters, but not in OXSAP hamsters, suggesting that HA regulation of energy balance had been compromised by the OXSAP lesion. Immunohistochemical results confirmed 63-96% loss of HDC-immunoreactivity in magnocellular neurons of the posterior hypothalamus in the OXSAP group. These data support the hypothesis that posterior hypothalamic HA neuron activity modulates metabolic activity during the breeding season in the Siberian hamster, although it is likely that ablation of additional neuronal phenotypes which express orexin-B (e.g. MCH) may contribute to the observed metabolic effects.

Related Products: Orexin-B-SAP (Cat. #IT-20)

Winter SS, Martin MM, Wallace DG (2007) Walking the Plank: Role of the medial septum in distance estimation. Neuroscience 2007 Abstracts 743.21/BBB15. Society for Neuroscience, San Diego, CA.

Summary: Controversy surrounds the role of the septohippocampal system in spatial orientation. Recent work has demonstrated that selective cholinergic deafferentation of the hippocampus impairs use of self-movement cues while sparing environmental cue use. Self-movement cues are generated from changes in position or direction. The current study examines the role of the septohippocampal cholinergic system in processing of self-movement cues related to changes in position or distance estimation in a food hoarding task. The probability of food hoarding has been shown to be influenced by travel distance and time to consume the food item. Long Evans female rats received either injections of 192 IgG-Saporin (SAP) or saline (SHAM) into the medial septum. Subsequent to recovery, rats were placed in a refuge on a 15 cm wide plank and allowed to traverse the plank to collect food pellets located at the end. Both the distance to the food pellet (2.4 vs. 4.8 m) and size of the food pellet (190, 500, 1000 mg) were varied across days. Differences in food hoarding probability were observed between groups. SAP rats were less likely to modify their food hoarding probability in response to changes in plank length relative to SHAM rats. These results are consistent with selective hippocampal cholinergic deafferentation producing deficits in processing self-movement cues related to distance estimation.

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

King M, Jentsch JD (2007) Prefrontal cortical norepinephrine depletion does not impair spatial working memory in rats. Neuroscience 2007 Abstracts 645.16/CCC18. Society for Neuroscience, San Diego, CA.

Summary: The midbrain dopamine neurons are thought to encode a reward prediction error signal (Schultz et al., 1997; Bayer & Glimcher, 2005). Parkinson’s disease (PD) is characterized by a loss of nigral dopamine neurons. Dopaminergic drugs including the dopamine precursor L-Dopa and D2 receptor agonists are taken to relieve disease symptoms. We hypothesized that patients with moderate PD (1) show atypical reinforcement learning off dopaminergic medication due to dopamine neuron loss, and (2) show more normal reinforcement learning on dopaminergic drug therapy. We developed a method to rapidly assess reinforcement learning in human subjects (Rutledge et al., SfN 2005) adapted from matching law tasks used in monkeys (Sugrue et al., 2004; Lau & Glimcher, 2005). On each trial, subjects choose one of two animated crab traps. Rewards (crabs worth $0.10) were scheduled for the two targets with different independent rates. Scheduled rewards remained available until the associated target was chosen, as in the original matching law experiments (Herrnstein, 1961). After a 5-minute training period, subjects completed 800 trials as we varied reward probabilities across blocks. PD patients (n=19) completed one session on and one off dopaminergic medication. Age-matched controls (n=21) and healthy young subjects (n=20) completed one session. We found that young and elderly control subjects had similar reinforcement learning rates, but learning rates were reduced in PD patients (when tested off medication). Learning rates in the same PD patients were restored to control levels when dopaminergic drugs were administered. We also found that the reinforcement-independent strategies of our subjects were influenced by dopamine. Young subjects tended to alternate targets independent of reward history. In contrast, elderly subjects (who suffer some dopamine neuron loss) had a tendency to perseverate in their choices. This tendency was increased in PD patients (off medication), but restored to control levels when dopaminergic drugs were administered. This effect on choice is not explained by existing models of dopamine function. These data support a role for dopamine in human reinforcement learning. Future models of decision making in reinforcement learning tasks must also account for a reward-independent effect of dopamine on choice behavior.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Nguyen WT, Buhalog A, Hendrickson M, Kalil RE (2007) On the survival of nestin-expressing neurons in the cholinergic basal forebrain after an immunolesion with 192-IgG-saporin. Neuroscience 2007 Abstracts 674.5/D24. Society for Neuroscience, San Diego, CA.

Summary: Nestin is a class VI intermediate filament protein that is widely accepted as a marker for uncommitted neural progenitor cells. However, we have described a class of cells in the cholinergic basal forebrain of the adult rat and human that express markers associated exclusively with neurons, e.g., NeuN, β-III tubulin, and choline acetyl transferase (ChAT) and also express nestin. We have termed these cells nestin-expressing neurons (NENs). To explore the possibility that the expression of nestin by NENs might provide a neuroprotective effect, we administered the immunotoxin 192-IgG-saporin (192-saporin). The toxin consists of a ribosome-inactivating protein coupled to a monoclonal antibody directed against the p75 nerve growth factor receptor (p75 NGFr). As a result, 192-saporin selectively destroys cells expressing this receptor, such as most of the cholinergic neurons in the basal forebrain. Two micrograms of 192-saporin in 6 µL of saline were injected unilaterally into the lateral ventricle of the brain in each of four adult Sprague-Dawley rats. Following a six day survival period, the rats were deeply anesthetized, perfused with 4% paraformaldehyde, and the brains were sectioned and immunostained for nestin and ChAT. After confirming that NENs, which were identified by the co-expression of nestin and ChAT, express the p75 NGFr, we determined the number of NENs in the medial septum and in the nucleus of the diagonal band as a percentage of all ChAT-positive neurons in these nuclei in rats treated with 192-saporin and in controls. We found no statistically significant difference in the proportion of NENs between rats that had received 192-saporin and controls. This result indicates that for the dose of 192-saporin and survival period used in these experiments, the expression of nestin does not confer a neuroprotective effect. Experiments using lower doses of 192-saporin and shorter survival times are underway.

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

Frachette M, Rennie K, Pappas BA (2007) Neonatal cholinergic lesion and environmental enrichment:behavior, neurogenesis and CA1 cytoarchitecture. Neuroscience 2007 Abstracts 691.9/M9. Society for Neuroscience, San Diego, CA.

Summary: The effects of neonatal cholinergic lesion and environmental enrichment on rat behaviour and hippocampal morphology were determined. Rats were injected with the immunotoxin 192 IgG- saporin (192S) on postnatal day 7, selectively lesioning forebrain cholinergic neurons as shown by their loss of acetylcholinesterase staining and p75NTR immunoreactive (IR) neurons. After weaning, the rats were placed in enriched or standard housing for 42 days. Enriched rats, regardless of whether or not they had received 192S, subsequently showed significantly enhanced performance on the working memory version of the Morris water maze. The lesion had no effect on spatial learning. However, the lesion significantly reduced doublecortin (DCX) IR cells in the dentate gyrus, indicating reduced hippocampal neurogenesis. Enrichment did not affect the number of DCX IR cells in lesioned rats whereas there was an apparent trend towards increased cells in non-lesioned rats. The number of DCX IR neurons in the enriched and impoverished lesion groups were identical and both were significantly less than the average for the enriched non-lesioned mean, suggesting that the lesioned rats were resistant to the effects of enrichment on neurogenesis. As shown by quantitative analysis of Golgi stained CA1 neurons, the cholinergic lesion affected CA1 cell morphology, reducing apical branches and total basal branch length. This was not prevented by enrichment. There were also a number of other effects selective for certain branches but these effects tended to be observed equally often in impoverished and enriched rats. In other words, the consequences of the cholinergic lesion were immune to the housing condition. Enrichment had several effects on hippocampal cytoarchitecture but these were selective for certain branch orders rather than global alterations. The most interesting consequence of enrichment, in terms of its implication for synapse density and information processing capability, was the increased spine density and spine number observed on some branches of the apical tree. This was evident only in the non-lesioned rats. Thus, neonatal cholinergic forebrain lesion reduces dentate gyrus neurogenesis, alters CA1 dendritic morphology but has no effect on spatial learning/memory. It also renders rats unresponsive to the effects of enrichment on dentate gyrus neurogenesis, CA1 dendritic spine morphology but not spatial learning/memory.

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