References

Krajewski SJ, Smith MA, Williams H, Ciofi P, Lai JY, Mcmullen NT, Rance NE (2011) Ablation of NK3 receptor-expressing KNDy neurons in the rat arcuate nucleus using [MePhe7]Neurokinin B-Saporin. Neuroscience 2011 Abstracts 712.09. Society for Neuroscience, Washington, DC.

Summary: A subpopulation of neurons expressing kisspeptin, neurokinin B and dynorphin (KNDy neurons) has been shown to reside within the arcuate nucleus of many mammalian species. Although these peptides are critical for reproductive function, the precise role of the arcuate KNDy neurons is not fully understood. Here we describe a method to ablate KNDy neurons based on their co-expression of the Neurokinin 3 receptor (NK3R, Burke et al., J. Comp. Neurol, 2006). Saporin, a molecular neurotoxin, was conjugated to [MePhe7]Neurokinin B, a selective NK3R agonist ([MePhe7]NKB-SAP, Advanced Targeting Systems, San Diego, CA). Binding studies revealed that the conjugation of saporin did not alter the affinity of [MePhe7]NKB to NK3R in rat cerebral cortex membranes. To investigate the specificity of this conjugate for ablation of NK3R neurons, stereotaxic surgery was used to bilaterally inject [MePhe7]NKB-SAP into the arcuate nucleus of female rats. Control rats were injected with saporin conjugated to a scrambled peptide (Blank-SAP, Advanced Targeting Systems). Rats were sacrificed 31-34 days later and the brains were processed for immunohistochemical studies. Nissl stained sections from [MePhe7]NKB-SAP-treated rats showed no signs of inflammation at the injection sites and no qualitative changes in cell density compared to Blank-SAP control rats. Immunohistochemistry revealed near-complete loss of NK3R-immunoreactive (ir) neurons throughout the arcuate nucleus of [MePhe7]NKB-SAP rats. When the injection site was dorsal to the arcuate nucleus, there was also variable loss of NK3R-ir cells in the lateral hypothalamus and zona incerta. In the arcuate nucleus, [MePhe7]NKB-SAP injections resulted in a 98% and 94% reduction in the number of kisspeptin and neurokinin B-ir neurons, respectively, compared to Blank-SAP controls. The number of dynorphin-ir neurons in the arcuate nucleus of [MePhe7]NKB-SAP-treated rats was reduced by 67%, a value consistent with the co-expression of NK3R on dynorphin neurons in our previous study (Burke et al., J. Comp. Neurol, 2006). In contrast, arcuate proopiomelanocortin and neuropeptide Y immunoreactivity were preserved in [MePhe7]NKB-SAP rats. Moreover, there was no difference in GnRH-ir fiber density in the median eminence between the two groups. These results document the utility of [MePhe7]NKB-SAP for selective ablation of NK3R-expressing KNDy neurons in rat hypothalamus. These rats were used to examine the role of KNDy neurons in the estrogen regulation of LH secretion and body weight in the female rat (see Smith et al., Soc. Neurosci. Abstr. 2011).

Related Products: Blank-SAP (Cat. #IT-21), NKB-SAP (Cat. #IT-63)

ATS Poster of the Year Winner

Roland JJ, Stewart AL, Savage LM, Servatius RJ, Pang KCH (2011) Reduced hippocampal acetylcholine efflux after medial septal-diagonal band (MSDB) GABAergic lesion is associated with impaired working memory: behavioral and neurochemical effects of physostigmine. Neuroscience 2011 Abstracts 513.10. Society for Neuroscience, Washington, DC.

Summary: The medial septum provides cholinergic innervation of the hippocampus and changes in hippocampal acetylcholine (ACh) have been tied to memory; deficits and enhancements in memory are correlated with decreases or increases of ACh, respectively. Damage of GABAergic MSDB neurons impaired spatial working memory in a delayed non-match to position task with a 30-s retention interval (DNMTP). Interestingly, lesions reduced maze activated hippocampal ACh efflux, but did not alter basal hippocampal ACh efflux. The current study has two aims. First, is performance impaired and ACh efflux reduced in a non-match to position task (NMTP) with a 0-s retention interval following GABAergic MSDB damage? Second, is performance on DNMTP improved by enhancing hippocampal ACh efflux? Male Sprague-Dawley rats received intraseptal PBS or GAT1-saporin (to damage GABAergic neurons) and a ventral hippocampal microdialysis cannula to assess ACh efflux. In Exp. 1, rats were trained on NMTP for 10 days and received microdialysis on either day 2 (early) or day 9 (late). GAT1-saporin rats were not behaviorally impaired and hippocampal ACh efflux was similar in both treatment groups. These results suggest that performance with a short retention interval (NMTP) is more independent of MSDB influences than training with a long retention interval (DNMTP). Exp. 2 was designed to determine whether the reduced ACh efflux is a critical factor in impaired DNMTP performance in rats with GABAergic MSDB damage. In Exp. 2, all rats will receive 10 day of DNMTP training. On days 8 and 9, rats will be administered (i.c.v.) either saline or the acetylcholinesterase inhibitor, physostigmine (5μg/μl). The effects of physostigmine on behavioral performance and hippocampal ACh efflux will be determined. We predict that physostigmine will increase ACh efflux but not improve behavior, suggesting that hippocampal ACh is not important for DNMTP performance. However, support that both MSDB cholinergic and GABAergic neurons are important for DNMTP performance would be seen if physostigmine increases ACh efflux and enhances DNMTP performance. In summary, damage of MSDB GABAergic neurons modulates hippocampal ACh efflux during performance of a working memory task. Whether hippocampal ACh release plays a critical role in impaired working memory will be answered by these studies.

Related Products: GAT1-SAP (Cat. #IT-32)

Winter SS, Köppen JR, Stout JM, Cameron HA, Wallace DG, Cheatwood JL (2011) Growth factor infusion increases BrdU-positive cells in the denervated medial septum following 192-IgG-saporin lesion. Neuroscience 2011 Abstracts 331.04. Society for Neuroscience, Washington, DC.

Summary: During the progression of Alzheimer’s Disease, degeneration of basal forebrain structures is associated with a decline in mnemonic function and frequently results in episodes of wandering behavior. Previous work has demonstrated that the septohippocampal cholinergic system uniquely contributes to rat spatial orientation. Enhancement of endogenous adult neurogenesis represents one potential method to restore function to the septohippocampal system. Therefore, we tested the hypothesis that co-infusion of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) would increase the number of new cells in the medial septum following a lesion of the cholinergic system produced by focal injection of the ribosome-inactivating selective immunotoxin 192-IgG-saporin in rats. For this, rats received injections of 192-IgG-saporin into the medial septum. At the same time, a cannula was placed in the lateral ventricle and attached to a subcutaneously-placed osmotic minipump containing either 1) EGF, bFGF, and bromodeoxyuridine (BrdU), or 2) BrdU alone. Infusion of growth factors and BrdU continued for a period of two weeks, at which point the pumps were removed. At 21 days following 192-IgG-saporin injury, rats were perfused following standard protocols. Cryostat sections were collected at 40 microns and were processed via double-fluorescent immunochemistry (IHC) using antibodies against BrdU and doublecortin (DCX). Photomicrographs of BrdU and DCX immunofluorescence were captured under epifluorescence and the number of BrdU-positive and DCX-positive cells was quantified. We detected significantly higher numbers of BrdU-positive cells in the medial septum of rats that received growth factors compared to rats that received BrdU-only (p<0.05). These results indicate that infusion of growth factors following 192-IgG-saporin lesion of the medial septum resulted in an increase in the number of new immature neurons in the medial septum. Studies aimed at determining the fate of these young neurons and their influences on spatial orientation are ongoing.

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Taxini CL, Bícego K, Takakura A, Moreira T, Gargaglioni L (2011) Noradrenergic neurons of the A5 region play a role on hypoxic ventilatory response in unanesthetized rats. Neuroscience 2011 Abstracts 345.09. Society for Neuroscience, Washington, DC.

Summary: The ventrolateral pons contains the A5 group of noradrenergic neurons which is involved in cardiorespiratory control. These cells are strongly activated by carotid body stimulation and display central respiratory modulation. Recently, we showed that A5 neurons contribute to the cardiorespiratory effects elicited by chemoreflex stimulation in anesthetized rats. In the present study, we assessed the role of A5 noradrenergic neurons on cardiorespiratory responses produce by hypoxia in unanesthetized rats. To selectively destroy noradrenergic neurons, we administered the immunotoxin anti-dopamine β-hydroxylase-saporin (anti-DβH-SAP, 200nL) bilaterally in the A5 region of male Wistar rats (n = 8). Hypoxia (7% O2, 30 min) produced an increase in ventilation (Ve) (1470 ± 141 mLkg-1min-1), respiratory frequency (RF) (179 ± 139 brethsmin-1) and heart rate (484 ± 29 bpm), without affect mean arterial pressure (MAP) in conscious rats. Bilateral destruction of the catecholaminergic A5 neurons reduced the hypoxia-induced hyperventilation (942 ± 110 mLkg-1min-1, p<0.05), increase in RF (139 ± 11 breathsmin-1, p<0.05) and tachycardia (399 ± 39 bpm, p<0.05). These results suggest that A5 noradrenergic neurons contribute to the increase in heart rate, ventilation and respiratory frequency during peripheral chemoreflex stimulation.

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

Wiater MF, Jansen H, Oostrom M, Li A-J, Dinh T, Ritter S (2011) Lesions targeting leptin-sensitive neurons in the mediobasal hypothalamus dissociate activity and temperature circadian rhythms. Neuroscience 2011 Abstracts 396.11. Society for Neuroscience, Washington, DC.

Summary: Previously we investigated the role of NPY and leptin sensitive networks in the mediobasal hypothalamus in sleep and feeding and found profound regulatory and circadian deficits. We propose that the MBH, particularly the arcuate nuclei (Arc), is required for the integration of homeostatic circadian systems including temperature and activity. We tested this hypothesis with the use of the saporin toxin conjugated to leptin (Lep-SAP) or a blank molecule with no known biological function or receptor (B-SAP) directed to the Arc. Lep-SAP binds to, is internalized by and destroys leptin receptor expressing neurons at the injection site. Lep-SAP rats became obese and hyperphagic and progressed through a dynamic phase to a static phase of growth similar to a ventromedial lesioned rat. Activity and temperature data were collected using intraperitoneal PDT-4000 Emitters with Vital View Data Acquisition Software (Mini Mitter, Philips Respironics, Bend, OR). Circadian rhythms were examined over 49 days during the static phase of obesity in B-SAP (n=10) and Lep-SAP (n=12) rats. Rats were maintained on a 12:12 light:dark (LD) schedule for 13 days and thereafter maintained in continuous dark (DD). After the first thirteen days of DD, food was restricted to four hours per day from 9AM until 1PM for ten days. Immediately thereafter, rats were fasted for three days to evaluate persistence of food-entrained rhythms. Using ClockLab software (Natick, MA) actograms and tempograms were generated as double raster plots. Lomb-Scargle periodograms were used to assess rhythms and their robustness. We found that Lep-SAP rats were arrhythmic for activity in DD, but that food anticipatory activity was nevertheless entrainable to the restricted feeding schedule and the entrained rhythm persisted during the subsequent 3-day fast. Thus, for activity, the light-entrainable oscillator, but not the food entrainable oscillator, was disabled by the MBH lesion. In contrast, temperature remained rhythmic in DD in the Lep-SAP rats, but did not entrain to restricted feeding. We conclude that the leptin-sensitive network of the Arc and MBH is required for entrainment of activity by photic cues and for entrainment of temperature by food and for the integration of these rhythms.

Related Products: Leptin-SAP (Cat. #IT-47), Blank-SAP (Cat. #IT-21)

Kalinchuk AV, Porkka-Heiskanen T, Mccarley RW, Basheer R (2011) Cholinergic neurons of the basal forebrain and nitric oxide-mediated regulation of sleep homeostasis. Neuroscience 2011 Abstracts 397.15. Society for Neuroscience, Washington, DC.

Summary: The levels of adenosine (AD) and inducible nitric oxide (NO) synthase (iNOS)-mediated NO increase during sleep deprivation (SD) in the basal forebrain (BF), and, with prolongation of SD, in the frontal cortex (FC). NO donor (DETA NONOate) infusion increases AD and sleep, while iNOS/NO inhibition prevents SD-induced AD increase, suggesting that iNOS/NO stimulates AD increase (Kalinchuk et al., 2006). iNOS induction during SD occurs in wake-active neurons in the BF and FC (Kalinchuk et al., 2010, 2011), however, neurotransmitter specificity of these cells has not described. The lesion of BF cholinergic cells attenuates both SD-induced AD increase and recovery sleep response (Kalinchuk et al., 2008). Hence in this study, we tested the role of cholinergic versus non-cholinergic neurons in iNOS/NO release in BF and FC and homeostatic sleep response. Methods. We performed two types of experiments. Experiment #1. Immunohistochemical detection of neurotransmitter specificity of cells inducing iNOS during SD. The brains of SD animals and their non-SD time-of-day matched controls were subjected to double-labeling with specific markers for iNOS, acetylcholinetransferase (ChAT), vesicular glutamate transporters (VGlut) and glutamate decarboxylase (GAD67). Experiment #2. The effects of SD on iNOS/NO production and the effect of NO-donor, DETA NONOate infusion on sleep were investigated before and after destruction of BF cholinergic neurons using 192 IgG-saporin. In both experiments male rats were implanted for electrographic recording and Experiment # 2 used guide cannula for microdialysis probes targeting BF and FC. In Experiment #2, recording of sleep-waking cycle, SD for 3h and infusion of DETA NONOate for 3h were performed on the same animals before and 2 weeks after targeted saporin injections. Results. Experiment #1. SD led to significant increases in number of iNOS+ cells in the BF and FC. Preliminary data showed that in the BF, in SD group, 96% of ChAT+ cells were also iNOS+, while in the non-SD group only 4% of ChAT+ neurons had weak iNOS+ staining. Numbers of iNOS+/ChAT+ cells positively correlated with SD-induced increase in theta power. Experiment #2. Before saporin injection, both SD and infusion of DETA NONOate induced significant increases in subsequent NREM sleep/NREM delta power (by 35/47% and 39/41%, respectively). After saporin injection, both recovery NREM sleep and DETA NONOate-induced sleep were significantly attenuated (8 and 4% increase as compared with baseline) and increases in delta power were totally blocked. Conclusions. We conclude that cholinergic neurons of the BF are important for iNOS/NO-mediated homeostatic sleep control.

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

Stewart AL, Roland JJ, Servatius RJ, Pang K (2011) Role of the medial septal-diagonal band nucleus in working memory: Effects of cholinergic or GABAergic lesions on memory demand and interference. Neuroscience 2011 Abstracts 513.09. Society for Neuroscience, Washington, DC.

Summary: The medial septum and diagonal band of Broca (MSDB), a major source of afferents to the hippocampal formation, is critical for learning and memory. The primary cells comprising the septohippocampal systems are cholinergic, GABAergic and glutamatergic. Selective damage of cholinergic MSDB neurons results in mild to no impairment of spatial working memory tasks, suggesting that non-cholinergic MSDB projections are important in learning and memory. Recently, we demonstrated that GABAergic MSDB lesions impair a delayed match to position task (DNMTP) with errors suggesting enhanced proactive interference. The current study assesses the effect of manipulating the intertrial interval (ITI) and retention interval (RI) on DNMTP performance in normal rats and those with cholinergic or GABAergic MSDB damage. In addition, activation of MSDB neurons on the last day of training will be assessed. Male Sprague Dawley rats receive sham, 192-IgG saporin (192-Sap) or GAT1-saporin (GAT1-Sap) administration into the MSDB before training on a DNMTP task using a T-maze. On the sample phase of each trial, rats are forced to one arm for reinforcement. Following an RI, a choice phase allows the rats to choose from both arms. Rats are reinforced for choosing the arm not entered during the sample phase. Following the choice phase, an ITI occurs before the sample phase of the next trial. Rats are trained one session per day, 12 trials per session, and 10 sessions. In a 2 x 2 experimental design, each rat is trained on either a 0 or 60s RI and a 0 or 60s ITI. Conditions with a long RI (60 s) are designed to tax working memory, whereas conditions with a similar RI and ITI are designed to increase interference. Immunocytochemistry for c-Fos is used to assess activation of cholinergic or GABAergic MSDB neurons following the last training session. As expected, our preliminary results show that sham rats performed better on 0 s than 60 s RI (0 s = 78% correct vs 60 s = 57%, both ITI’s pooled). Analysis of the 0 s RI demonstrates that performance in conditions with different RI and ITI was better than when RI and ITI were similar (0 s RI/60 s ITI = 74% vs 0 s RI/0 s ITI = 67%). Further analysis of the 60 s RI was difficult due to the near chance performance. Rats treated with either intraseptal 192-Sap or GAT1-Sap were impaired on the 0 s RI/60s ITI condition (Sham: 85%; 192-Sap: 65%; GAT1-Sap: 72%). However, only the 192-Sap rats were impaired in the 0 s RI/0 s ITI condition (Sham: 71%; 192-Sap: 62%; GAT1-Sap: 69%). Anatomical studies are currently underway. The results of this study will further elucidate the role of MSDB neurons in two aspects of working memory: memory demand and interference.

Related Products: 192-IgG-SAP (Cat. #IT-01), GAT1-SAP (Cat. #IT-32)

Donahue RR, Corder GF, Mcnamara KC, Wiley RG, Taylor BK (2011) Transmission of neuropathic pain by spinal neurons expressing the NPY Y1 receptor. Neuroscience 2011 Abstracts 179.16. Society for Neuroscience, Washington, DC.

Summary: Endogenous neuropeptide Y (NPY) acts at Y receptors in the dorsal spinal cord to exert a tonic inhibitory control of chronic allodynia (Solway et al, PNAS 108:7224-9, 2011). In this and the adjacent presentation, we tested the hypothesis that NPY does this by inhibiting Y1 receptors on pain transmission neurons or on central terminals of primary afferent neurons. We selectively lesioned cells expressing the NPY receptors in the dorsal horn with intrathecal administration of the NPY-conjugated ribosomal toxin, NPY-saporin. NPY-saporin significantly reduced the population of Y1 receptors in the lumbar dorsal horn by over 50%. Neither NK1 receptors in the dorsal horn, nor neuronal counts in the DRG were affected, suggesting a specific effect on Y1+, NK1- neurons in the dorsal horn, while sparing Y1+ central presynaptic terminals. Fourteen days later, we ligated the tibial and common peroneal branches of the sciatic nerve (spared nerve injury, SNI), and evaluated the development of allodynia and hyperalgesia on post-SNI days 1, 3, 5, 7, 14, 21, 28, 35, and 42. When compared to saporin controls, NPY-saporin (1000 ng) decreased mechanical allodynia (von Frey threshold), cold allodynia (paw withdrawal response to application of a drop of acetone) and mechanical hyperalgesia (paw response to blunt pin). This effect began three days after SNI and lasted until forty two days after SNI. When injected in uninjured rats, NPY-saporin did not disrupt motor coordination (accelerating rotarod), baseline heat or mechanical thresholds, or animal activity levels. We conclude that Y1-expressing cells in the dorsal horn exert a tonic facilitatory control of neuropathic pain, and partially mediate the inhibitory actions of NPY.

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Corder GF, Donahue R, Winter MK, Chen W, Mccarson KE, Marvizon J, Taylor B (2011) Activation of postsynaptic NPY Y1 and presynaptic Y2 receptors reduce spinal nociceptive transmission. Neuroscience 2011 Abstracts 179.17. Society for Neuroscience, Washington, DC.

Summary: Exogenous (Intondi et al, Neuroscience, 2008) and endogenous (Solway et al, PNAS 108:7224-9, 2011) neuropeptide Y (NPY) acts at Y1 and Y2 receptors in the dorsal horn (DH) to inhibit hypersensitivity to mechanical and thermal stimuli. The adjacent poster (Donahue, et al, SFN 2011) describes our use of a targeted NPY-saporin neurotoxin approach to selectively remove spinal cord (SC) neurons expressing the Y1 receptor — the data implicate a contribution of Y1-expressing, pain transmission neurons to behavioral signs of persistent pain. To determine whether persistent noxious input is associated with a compensatory increase in NPY-mediated inhibitory signaling (presumably at Y1-expressing DH neurons), we performed GTPγS binding assays in SC slices taken from animals following the intraplantar (i.pl) injection of complete Freund’s adjuvant (CFA). CFA significantly reduced the EC50 of Y1 agonist (Leu31,Pro34-NPY)-induced [35S]GTPγS binding in ipsilateral DH to 0.24 ± 0.17 μM, as compared to sham (1.38 ± 0.51 μM). This support the hypothesis that injury increases in the efficiency of coupling between Y1-receptors and G-proteins. To determine whether compensatory NPY inhibition occurs at presynaptic sites, we studied the activity of presynaptic Y2 receptor in NPY-saporin-treated rats. Intrathecal injection of the Y2 receptor antagonist BIIE0246 reduced von Frey thresholds (saporin group from 1.3±0.4 to 0.6 ±0.1g; 750 ng NPY-saporin group from 5.4±1.0 to 1.2±0.2g, p<0.05), suggesting that presynaptic Y2 receptors contribute to a tonic endogenous inhibition of inflammatory pain. In support of this hypothesis, BIIE0246-induced hyperalgesia (21 days after CFA) significantly increased the Emax of Y2 agonist (PYY3-36)-induced [35S]GTPγS binding. We next determined whether NPY acts at presynaptic terminals of primary afferent neurons to reduce the release of substance P (SP). First, in both the i.pl carrageenan and CFA models of inflammatory pain, intrathecal administration of NPY reduced in vivo neurokin-1 (NK1) receptor internalization (an indirect measure of functional SP release). Second, application of either (Leu31,Pro34)-NPY) or PYY3-36 to spinal cord slices concentration-dependently reduced NK1 internalization in the ipsilateral dorsal horn evoked by electrical stimulation of the dorsal root (1000 pulses of 20 V, 0.4 ms at 100 Hz); these effects were reversed by the Y1 antagonist BIBO3304. We conclude that injury up-regulates post-synaptic Y1 and pre-synaptic Y2 spinal inhibitory mechanisms to reduce behavioral signs of persistent pain.

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Sinha SP, Roland JJ, Servatius RJ, Pang KCH (2011) The role of medial septal/diagonal band GABAergic neurons in proactive interference: Effects of selective immunotoxic lesions in latent inhibition. Neuroscience 2011 Abstracts 199.22. Society for Neuroscience, Washington, DC.

Summary: The medial septum/diagonal band (MSDB) is a critical structure for learning and memory, yet the functional contributions of its individual neuronal populations (including cholinergic, GABAergic, glutamatergic and peptidergic cells) are still being characterized. Recent studies have implicated a contributing role for the GABAergic MSDB neuronal population, as selective immunotoxic GABAergic lesions of the MSDB (with GAT1-saporin) produce behavioral impairments in spatial and instrumental tasks. Compared to intact controls, rats with GABAergic MSDB lesions are impaired in learning new spatial locations in a delayed match to position procedure and also exhibit a slower rate of extinguishing a previously acquired avoidance response – behaviors that are consistent with an exacerbation of proactive interference. To further establish the role of these neurons in proactive interference, this study examined the effects of selective GABAergic MSDB lesions in latent inhibition (LI) of the classically conditioned eyeblink response. LI in delay eyeblink conditioning is a phenomenon in which pre-exposure to the conditioned stimulus (CS) interferes with the subjects’ ability to subsequently associate the CS with an unconditioned stimulus (US), resulting in slower acquisition of the conditioned response (CR). We hypothesized that if damage of GABAergic MSDB neurons increases proactive interference, then rats with selective lesions of these neurons would show facilitated LI. Male Sprague-Dawley rats (n=18) were administered either phosphate-buffered saline or GAT1-saporin via intracranial injection into the MSDB. After 7-10 days of recovery, electrodes were implanted into the upper eyelids of the rats for delivery of US and EMG recording. Conditioning began after another 5-7 days of recovery, with Day 1 consisting of 30 minutes of acclimation to the conditioning context. Day 2 began with either 30 presentations of the CS (82dB, 500ms white noise, 25 – 35s ITI) or context pre-exposure of equal duration, followed immediately by 100 paired CS-US trials (82 dB, 500ms white noise co-terminating with a 10V, 10ms square-wave stimulus). In preliminary results, intraseptal GAT1-saporin did not alter CR acquisition in context pre-exposed rats. Rats with GABAergic MSDB lesions continued to exhibit latent inhibition. These preliminary results do not support the idea that damage of GABAergic MSDB neurons increase proactive interference of the classically conditioned eyeblink response. Future studies will examine whether manipulations of the number of CS pre-exposures would facilitate LI in rats with GABAergic MSDB lesions.

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