sfn2005

Gibbs RB, Fitz NF, Johnson DA (2005) Cholinergic lesions produce selective effects on cognitive performance in rats. Neuroscience 2005 Abstracts 881.1. Society for Neuroscience, Washington, DC.

Summary: Cholinergic projections from the basal forebrain play an important role in cognitive processes; however, the degree to which damage to specific projections contributes to impairment within specific cognitive domains is unclear. In the present study, cholinergic projections to the hippocampus and/or frontal cortex of young adult, ovariectomized Sprague-Dawley rats were selectively destroyed by injecting 192 IgG-saporin (SAP) into the medial septum (MS), the nucleus basalis magnocellularis (NBM), or both the MS and NBM (MSNBM). Controls received injections of sterile saline. Animals were then tested for learning and memory impairments using a series of tasks, including a delayed matching-to-position (DMP) T-maze task, an operant configural association (CA) negative patterning task, and a 12-arm radial maze (RAM) task, administered in that order. Results reveal different effects of the lesions on the different tasks. For example, SAP lesions of the MS, as well as combined lesions of MS and NBM significantly impaired acquisition the DMP task; however, once animals had reached criterion, cholinergic lesions did not alter decrements in performance produced by increasing the intertrial delay. In contrast, SAP lesions of the MS had no significant effect on acquisition of the CA task, although combined lesions of MS and NBM produced a trend toward impairment on the CA task among animals with the most severe cholinergic depletion. Likewise, combined lesions significantly impaired acquisition of the RAM task. In general, combined lesions produced greater impairments than lesions of either the MS or NBM alone. Significant correlations between acquisition of the DMP and RAM tasks and ChAT activity in the hippocampus, frontal cortex, and occipital cortex, were also detected. These data demonstrate that removal of cholinergic projections to the hippocampus and frontal cortex produce cognitive impairments that are lesion specific as well as task dependent.

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Bailey AM, St Germain J, Tyler MM (2005) 192 IgG-saporin lesions to the nucleus basalis magnocellularis (NBM) do not disrupt the retention of learning set formation. Neuroscience 2005 Abstracts 881.2. Society for Neuroscience, Washington, DC.

Summary: Male Long Evans rats (Rattus norvegicus) were used to investigate the role of the nucleus basalis magnocellularis (nBM) in the retention of a previously acquired learning set rule. All rats had successfully acquired an olfactory discrimination learning set by demonstrating above chance performance on trial 2 across 42 olfactory discrimination problems. Following the initial acquisition of learning set, animals were given bilateral 192 IgG-saporin (0.375 µg/µl; 0.4 µl per hemisphere) lesions to the nBM. Assessment of open field activity indicated that there were no group differences in general activity levels or emotionality before or after surgery. Retention of learning set was tested 10 days following surgery with 20 novel, odor-unique olfactory discrimination learning set problems. Control and nBM lesioned animals performed significantly higher than expected by chance on trial 2 of the novel problems suggesting retention of a learning set hypothesis. However, rats with 192 IgG-saporin nBM lesions performed learning set at a significantly lower level than control animals as measured by trial 2 percentage correct. Results suggest that damage to the nBM disrupts general performance on a cognitively demanding task, but does not block retention of the learning set rule.

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Ferry B, Herbeaux K, Petoukhova-Traissard N, Galani R, Cassel J, Majchrzak M (2005) Facilitation of conditioned odor aversion by entorhinal cortex lesion in the rat is reversed by cholinergic lesion in the basal forebrain. Neuroscience 2005 Abstracts 881.6. Society for Neuroscience, Washington, DC.

Summary: In the rat, conditioned odor aversion (COA) corresponds to the avoidance of an odorized-tasteless solution (conditioned stimulus, CS) previously associated with toxicosis (unconditioned stimulus, US). Evidence suggests that the entorhinal cortex (EC) is part of the neural substrate involved in the acquisition of COA. Indeed, we showed that EC lesion facilitated CS-US association and rendered it resistant to lengthening of the interstimulus interval (ISI). This facilitation phenomenon might correspond to a lengthening of the olfactory CS memory trace, rendering the association with the subsequent US possible. Because i) all our EC-lesioned rats showed septo-hippocampal cholinergic sprouting, and ii) scopolamine infusions into the dentate gyrus reversed performance in EC-lesioned but not in sham-operated rats in a spontaneous olfactory preference test, we suggested that COA facilitation resulted from enhanced cholinergic activity in the hippocampus. In order to test this hypothesis, we studied the effect of a cholinergic basal forebrain lesion combined to an EC-lesion during COA. Male Long-Evans rats subjected to bilateral EC lesions and intraventricular infusions of the selective toxin 192 IgG-saporin received odor-US pairings with a short or long ISI. Results showed that sham-lesioned rats displayed COA with the short, but not the long ISI, whereas EC-lesioned rats showed COA with both ISI. More interestingly, rats with double lesions did not differ from controls, suggesting that the cholinergic lesion suppressed the effect of EC-lesions. These results strongly suggest that the facilitative effects observed in EC-lesioned animals during COA are due, at least in part, to the septo-hippocampal cholinergic sprouting elicited by the EC lesion. Moreover, they suggest that the hippocampal cholinergic system is involved in the control of memory processes underlying the association between the olfactory CS and the US during acquisition of COA.

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Kolasa K, Parsons D, Harrell LE (2005) Time-dependent neurotrophins effect on cholinergic denervation and hippocampal sympathetic ingrowth following 192 IgG-saporin lesioning of medial septum. Neuroscience 2005 Abstracts 1004.4. Society for Neuroscience, Washington, DC.

Summary: In rat,injection of specific cholinotoxin,192 IgG-saporin into the medial septum results not only in a selective denervation of hippocampus(CD),but in an ingrowth of peripheral sympathetic fibers,originating from the superior cervical ganglion,into the hippocampus.This process has been termed hippocampal sympathetic ingrowth(HSI).A similar process,in which sympathetic noradrenergic axons invade hippocampus,may also occur in Alzheimer’s disease(AD). The severity of cognitive decline in AD patients has been linked to multiple factors including cholinergic and neurotrophic factors and their receptors,which undergo selective alterations throughout the progression of AD.It is known that the sites of synthesis of NGF(nerve growth factor),BDNF(brain derived-neurotrophic factor)and LIF (leukemia inhibitory factor)in rat septo-hippocampal system are predominantly hippocampal neurons.By using 192 IgG-saporin we have been able to mimic some of the cardinal features of AD e.x.cholinergic denervation and hippocampal sympathetic ingrowth and to study their effect on neurotrophins in dorsal hippocampus.Thus,2,8,and 12 weeks after injection of 192 IgG-saporin we measured NGF, BDNF and LIF protein and mRNA expression using Western blot and RT-PCR techniques, respectively.Choline acetyltransferase activity(ChAT) and norepinephrine(NE) concentration was also detected. Significant alterations were found in NGF and LIF protein expression(decrease at 8 weeks and increase at 12 weeks post lesions)in HSI group. Significant decrease of BDNF(mature form) protein expression was found in CD group over whole period of time. There was significant decrease found in BDNF mRNA expression in CD,with normalization in HSI group 12 weeks post lesions. Results of the study suggest that neurotrophins are affected by cholinergic denervation and may play an important role in regulation and development of HSI,which might be a beneficial phenomenon for restoration at least some of cognitive function.

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Truitt WA, Oberlin BG, Dietrich AD, Fitz SD, Shekhar A (2005) Neurokinin 1 receptor containing interneurons of the BLA are putative candidates for the inhibitory component of feed-forward inhibition from the mPFC to the BLA. Neuroscience 2005 Abstracts 796.12. Society for Neuroscience, Washington, DC.

Summary: The amygdala and in particular the basolateral nucleus of the amygdala (BLA) is a central site for fear and anxiety. The BLA is under tonic inhibition by a network of inhibitory interneurons. Additionally, cortical inputs can both excite or inhibit the output of the BLA, resulting in increases or decreases in anxiety/fear-like behaviors. In particular mPFC inputs to the BLA can suppress BLA output and inhibit fear conditioning. However, the mechanism by which this occurs is not fully understood. Evidence from electrophysiological studies suggests a feed forward inhibitory relationship between the mPFC and the BLA. This feed forward inhibition putatively occurs by mPFC-glutamatergic inputs exciting GABAergic interneurons of the BLA, which in turn suppress firing of the BLA projection neurons. However, tracing studies demonstrate that the vast majority of mPFC inputs to the BLA form synapses with dendritic spines, which have been reported to exist only on projection neurons of the BLA. Here we present data that suggests a specific subclass of BLA interneurons, those that express neurokinin 1 receptors (NK-1r) are likely candidates for the inhibitory component of the feed forward inhibition described above. Here we report that, in the rat, the NK-1r containing BLA-interneurons contain dendritic spines and NMDA receptors. Furthermore, we report that in anesthetized rats disinhibition of mPFC neurons by injections of bicuculline methiodide (50 pmol), leads to cFos induction in 25 – 50% of the NK-1r containing interneurons in the BLA, while 0% of the NK-1r interneurons expressed cFos following vehicle injections. Furthermore, selective ablation of these NK-1r containing BLA-interneurons (by use of the targeted toxin, SSP-Saporin) suppressed anxiolytic-like effects of familiarity in the SI test. Collectively, these data suggest the NK-1r containing interneurons of the BLA may respond to glutamatergic inputs from the mPFC and may be involved in a mPFC-BLA anxiety or fear regulating pathway.

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

Datta S, Kline IV RH, Wiley RG (2005) Increased formalin behavior after selective destruction of μ opiate receptor-expressing dorsal horn neurons: impaired descending analgesic control?. Neuroscience 2005 Abstracts 623.15. Society for Neuroscience, Washington, DC.

Summary: Spinal intrathecal injection of dermorphin-saporin (derm-sap) selectively destroys dorsal horn neurons expressing the mu-opiate receptor (MOR). In the present study, we sought to determine the effect of derm-sap (500 ng, i.t.) on responses to intraplantar formalin injection (25 ul of 5%). After formalin injection, rats were immediately placed into a clear observation chamber with a video camera beneath the floor. Rats were videotaped for 90 minutes and their behavior scored offline for one minute out of every 5 minutes. 120 minutes after formalin injection rats were anesthetized with pentobarbital and perfused with formalin. Spinal cord sections were stained for MOR and cholecystokinin (CCK) using standard immunoperoxidase techniques on adjacent 40 um sections from L4 spinal segment. Coded sections were used to assess MOR staining intensity by quantitative densitometry. Derm-sap treated rats showed no separation between phase I and II and spent more time than vehicle controls licking/guarding/biting the injected hindpaw during both phase I and II. Derm-sap significantly decreased dorsal horn MOR. Staining for CCK showed time dependant changes after derm-sap which was not present in PBS controls. These same derm-sap treated rats performed normally on hotplate at 44, 47 and 52 C and had normal analgesic responses to systemic morphine on 44, 47 and 52 C hotplates. We interpret these data to indicate that loss of the dorsal horn MOR-expressing neurons reduces the effect of descending analgesic mechanisms. Supported by NIH R21-DA14380 and Department of Veterans Affairs.

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Vera-Portocarrero LP, Xie Y, King T, Lai J, Porreca F (2005) Facilitatory influences from the rostral ventromedial medulla (RVM) are required for pancreatic nociception. Neuroscience 2005 Abstracts 623.18. Society for Neuroscience, Washington, DC.

Summary: Pain is a frequent complaint of patients with pancreatitis or pancreatic cancer. An animal model of pancreatitis induced by dibutyltin dichloride (DBTC) is characterized by abdominal hypersensitivity to mechanical stimuli that appears by day 3 after induction of pancreatitis and persists for at least 10 days. We have used this model to evaluate the role of descending pain modulatory pathways from the RVM in the processing of visceral pain. Pancreatitis was induced in rats by a single tail vein injection of DBTC. Animals were monitored for mechanical sensitivity of the abdominal area as an index of pancreatic nociception using von Frey hairs applied to the surface of the abdomen and recording the frequency of withdrawals from stimulation. Six days after DBTC injection, when mechanical hypersensitivity was fully developed, lidocaine, or saline, was microinjected into the RVM. Lidocaine, but not saline, given into the RVM produced a time-related reversal of mechanical hypersensitivity which peaked by 20 min after injection in animals with pancreatitis. RVM lidocaine had no effect on rats without pancreatitis. A second group of rats received a single microinjection of the cytotoxin dermorphin-saporin into the RVM in order to ablate mu opioid receptor expressing cells that have been proposed to drive descending pain facilitation. 28 days later, the rats received DBTC and their response to mechanical stimulation was monitored daily. These rats showed mechanical hypersensitivity on day 3 after DBTC, but the sensory threshold reverted to normal level by day 6, while rats that had been pretreated with dermorphin, saporin, or water exhibited persistent mechanical hypersensitivity after DBTC out to day 10. These data suggest that a blockade of the descending input from the RVM by lidocaine is sufficient to block the pancreatitis-induced visceral pain, and that the mu opioid receptor expressing cells in the RVM are critical for the persistent pain state.

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Kozak R, Parikh V, Martinez V, Brown H, Bruno JP, Sarter S (2005) What does acetylcholine do in the posterior parietal cortex (PPC)? Attentional performance-associated increases in PPC ACh efflux. Neuroscience 2005 Abstracts 644.1. Society for Neuroscience, Washington, DC.

Summary: Medial prefrontal cortex (mPFC) ACh efflux has been demonstrated to mediate attentional performance, particularly under conditions that require increases in attentional effort or the processing of distractors. Activation of the mPFC, in part as a result of cholinergic activity, is thought to orchestrate top-down effects for optimization of input processing elsewhere in the cortex. We previously demonstrated that mPFC cholinergic mechanisms influence PPC ACh efflux, suggesting that PPC ACh efflux is a component of the prefrontal circuitry mediating top-down effects. The present experiment was designed to characterize attentional performance-associated increases in PPC ACh efflux in animals performing a regular sustained attention task, following the presentation of a visual distractor, and following loss of cholinergic inputs to the mPFC. Attention task-performing animals were equipped with a guide cannula for insertion of a microdialysis probe and to collect dialysates in the PPC. Cholinergic projections to the mPFC were lesioned bilaterally by infusing 192-IgG saporin into the mPFC. Regular attentional performance was associated with increases in PPC ACh efflux that mirrored those observed previously in the mPFC. In contrast to evidence indicating a cholinergic role in the processing of distractors in the mPFC, PPC ACh efflux was not affected by the distractor and associated impairments in performance. The performance effects of the distractor were augmented in animals with mPFC cholinergic deafferentation. Performance-associated increases in PPC ACh efflux of deafferented animals were higher following the presentation of the distractor than in intact rats. These data support the hypotheses that mPFC cholinergic inputs contribute to the suppression of the effects of distractors and to the recruitment of posterior cortical cholinergic inputs to optimize processing under challenging conditions.

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Butt AE, Cabrera S, Chavez C, Corley S, Cortez A, Figueroa J, Kitto M, Torner E (2005) Basal forebrain cholinergic lesions produce a dissociation of impairment in delay and trace conditioning in rats. Neuroscience 2005 Abstracts 644.2. Society for Neuroscience, Washington, DC.

Summary: Recent research suggests that Pavlovian trace conditioning, but not delay conditioning, requires awareness or attention, where these processes appear to depend on specific brain systems. For example, Clark, Manns, and Squire (2002) have shown that although amnesiac humans with damage to the hippocampus (HPC) acquire a normal conditioned response (CR) in delay conditioning paradigms where the conditioned stimulus (CS) and unconditioned stimulus (US) partly overlap, they fail to acquire the CR in trace conditioning paradigms where the CS and US are separated in time. Han and colleagues (2003) have shown that the anterior cingulate cortex (ACC) is similarly necessary for trace but not delay conditioning in rats. The medial prefrontal cortex (mPFC) is also involved in trace but not delay conditioning (Kronforst-Collins & Disterhoft, 1998). The basal forebrain cholinergic system (BFCS) has projections to mPFC, ACC, and HPC. Given that each of these regions is critical for trace but not delay conditioning, we hypothesized that lesions of the BFCS using 192 IgG-saporin (SAP) would selectively impair trace but not delay appetitive conditioning in rats. Rats received bilateral injections of SAP or saline only (control group) into BFCS prior to conditioning with a tone CS and sucrose pellet US in either a delay or 10 s trace conditioning paradigm. Preliminary results support this hypothesis. Compared to controls, rats in the BFCS lesion group showed moderate impairment in delay conditioning but more severe impairment in the trace conditioning paradigm. Rats in both groups showed an increase in differential responding to the CS in the delay paradigm, although the BFCS lesion group showed less conditioned responding than controls. In contrast, only the controls showed progressive differential responding to the CS in the trace conditioning paradigm. These data suggest that the BFCS contribute critically to the maintenance of attention in Pavlovian trace conditioning.

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

Strait TA, Montoya D, Pang KCH (2005) Role of the medial septum in a repeated acquisition task. Neuroscience 2005 Abstracts 647.14. Society for Neuroscience, Washington, DC.

Summary: The medial septum/diagonal band of Broca (MSDB) provides a major afferent pathway to the hippocampus and both regions are important in learning and memory. The two major projection cells of the MSDB are cholinergic and GABAergic neurons. Although nonselective lesions of the MSDB impair spatial memory, the role of the different MSDB neuronal population in memory is an active area of research. In the present study, rats with preferential cholinergic or GABAergic lesions of the MSDB will be tested on the repeated acquisition task. The task assesses how well a rat can learn the location of a reward that changes from day to day. All sessions are performed on an 8-arm radial arm maze using one arm for reward. Each daily session consists of 5 trials with rats starting from a different arm on each trial. Rats are tested for a total of 9 days; each day a new rewarded arm is used. Our preliminary data suggest that rats with selective cholinergic lesions using 192-IgG saporin are not impaired in acquisition of the task. These results with selective cholinergic lesions contrast with our previous work showing that preferential GABAergic MSDB lesions impair performance of a repeated acquisition task in a water maze. We are currently investigating the effects of preferential GABAergic MSDB lesions on this task. Our preliminary data suggests that cholinergic and GABAergic MSDB neurons may have differential roles in acquisition of a spatial memory task.

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