References

Isaac M, Pearce JM, Muir JL (2001) Visual orienting response and the nucleus basalis of Meynert. Neuroscience 2001 Abstracts 313.2. Society for Neuroscience, San Diego, CA.

Summary: The nucleus basalis of Meynert (nbM), within the basal forebrain, contains a mass of large cholinergic neurones that send axons throughout the cortex. Previous studies have shown the nbM may be involved in attentional processing. The current study attempted to look at the effects of a cholinergic specific nbM lesion (using 192 IgG-saporin) on an attentional task involving two different serial conditioning schedules. In the Consistent condition a light (10s) was followed by a tone (10s), that signaled food. In the Inconsistent condition the light was presented alone for some trials and for other trials the light was followed by the reinforced tone. The orienting response towards the light was measured at three points throughout its presentation: within the first two seconds (light onset) and then twice within the post-onset period (2s-10s). According to the Pearce-Hall theory (1980), animals pay more attention to the light when it is followed by unpredictable events (Inconsistent condition) rather than predictable events (Consistent condition). Accordingly, the orienting response directed towards the post-onset light (2-10s), was stronger for sham operated rats that were trained with the Inconsistent than the Consistent condition. By contrast by the lesioned group was weak and at a similar level for both groups. These results suggest that the nbM lesions prevented enhanced attention to the light in the Inconsistent condition. These findings support the claim that the nbM is important for enhancing attention to stimuli (Chiba et al, 1995).

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Gadd CA, Murtra P, Hall CN, Gana M, Webber MJ, De Felipe C, Hunt SP (2001) NK1-expressing neurons critical for morphine reward behaviors in mice: C-fos expression and ablation of NK1-expressing neurons. Neuroscience 2001 Abstracts 224.13. Society for Neuroscience, San Diego, CA.

Summary: We have previously shown using conditioned place preference (CPP) that mice lacking the preferred receptor for substance P (NK1) show an absence of the rewarding response to morphine as well as reduced conditioned place aversion and physical withdrawal signs following chronic opiate treatment (Nature 405, 180-183). To locate those regions of the brain in which NK1-expressing neurons are crucial for opiate-mediated reward behavior, we examined the expression of c-Fos following acute (10 mg/kg IP) and chronic (increasing doses from 10 to 100 mg/kg IP) morphine administration, and following CPP to morphine (7.5 mg/kg) in wild-type and NK1 knockout mice. The expression of c-Fos in the brains of mice treated with chronic or acute morphine treatment was similar in both genotypes. Moreover, NK1-expressing neurons in the striatum and nucleus accumbens (NAc) were never seen to co-express c-Fos immunoreactivity. In contrast, the expression of c-Fos following the CPP protocol was significantly different between genotypes with a reduced number of c-Fos positive neurons in NK1 knockout mice in the amygdala and hippocampus but not in the NAc or dorsomedial striatum (DMS). We next investigated the effects of selective ablation of NK1 expressing neurons by injecting substance P-saporin into these regions. Our results suggest that destruction of these cells in the amygdala but not in the NAc or DMS causes a reduction in CPP to morphine without affecting anxiety levels or locomotor activity.

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Camara AL, Pereira EF, Alkondon M, Randall WR, Castro NG, Cintra WM, Albuquerque EX (2001) Septal innervation of the hippocampus regulates expression α7 nicotinic receptors in CA1 and CA3 pyramidal neurons. Neuroscience 2001 Abstracts 145.1. Society for Neuroscience, San Diego, CA.

Summary: To investigate the effects of septal innervation on expression of α7 nicotinic receptors (nAChRs) in CA1 and CA3 pyramidal neurons in the hippocampus, the patch-clamp technique and confocal microscopy were applied to organotypic hippocampal cultures and septal-hippocampal co-cultures. In the co-cultures, septal fibers labeled with DiI were visualized in the hippocampus. Field stimulation of septal fibers also resulted in postsynaptic currents that could be recorded from CA1 and CA3 pyramidal neurons in the hippocampus. These currents had glutamatergic, GABAergic and cholinergic components. The latter originated most likely from the septal cholinergic neurons that were labeled in situ with the cholinergic marker Cy3-192 IgG. α7 nAChRs in the somatodendritic region of CA1 and CA3 pyramidal neurons in the hippocampus in cultures and co-cultures were activated by the α7 nAChR agonist choline, which elicited type IA currents, and were visualized by labeling with rhodamine-conjugated α-bungarotoxin (Rho-α-BGT). After 21 days in vitro, the amplitude of type IA currents was substantially smaller in pyramidal neurons in septal-hippocampal co-cultures than in hippocampal oragnotypic cultures. Labeling of the somatodendritic region of hippocampal pyramidal neurons with Rho-α-BGT was also less intense in the organotypic co-cultures than in cultures. These results suggest that functional septal innervation of the hippocampus regulates the expression of α7 nAChRs in hippocampal pyramidal neurons.

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Yan J, Price DL, Koliatsos VE (2001) Nestin expression in neurons of the medial septum/diagonal band in the adult rat. Neuroscience 2001 Abstracts 25.9. Society for Neuroscience, San Diego, CA.

Summary: Nestin is a marker for neuronal precursor cells in normal animals. In adult animals, nestin (+) cells are limited to the ventricular wall, hippocampus and the rostral migratory stream, where neurogenesis is known to persist throughout life. We are now reporting the existence of nestin (+) cells in the medial septum/diagonal band area based on immunocytochemical staining with different nestin antibodies. Many of these cells colocalize ChAT and nestin. In addition, some nestin (+) cells can be traced with the carbocyanin dye SP-DiI injected into the lateral ventricle to label cell lineages originating in the ependymal layer. Medial septal/diagonal band lesions by complete fimbria-fornix transections or 192-IgG-saporin conjugate injections into the ventricle cause an increase in BrdU (+) and nestin (+) cells in medial septum/diagonal band especially in anterior planes. We are currently double labeling the sections with BrdU and nestin or TUJ1. Our working hypothesis is that there may be ongoing neurogenesis in the medial septum/diagonal band in the adult brain, especially after injury or under pathological conditions and this may have implications for pathogenesis and treatment of Alzheimer’s disease.

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Gu JG, Nakatsuka T, Tanaka E, Takeda D, Jennifer LX (2001) Capsaicin-sensitive inhibitory pathway in rat spinal cord dorsal horn. Neuroscience 2001 Abstracts 158.13. Society for Neuroscience, San Diego, CA.

Summary: The inhibitory system in the spinal cord plays an important role in regulating nociceptive sensory inputs. Here we examined inhibitory synaptic activity in lamina V neurons of the spinal dorsal horn following the activation of capsaicin VR1 receptors. Experiments were performed with spinal cord slice preparations and inhibitory postsynaptic currents (IPSCs) were recorded using patch-clamp technique. Bath application of capsaicin (2 μM) increased the amplitude and frequency of GABAergic and glycinergic spontaneous IPSCs in the majority of lamina V neurons tested. The effects of capsaicin were completely antagonized by capsazepine (10 μM), and were also blocked in the presence of tetrodotoxin (0.5 μM). However, when CNQX (20 μM) and APV (100 μM) were used to block glutamatergic synaptic transmission, the effects of capsaicin were not abolished. Furthermore, after the injection of IB4-saporin into sciatic nerve to remove IB4-positive C-primary afferent terminals, capsaicin still increased sIPSC frequency in the presence of CNQX and APV. These results suggest that inhibitory pathway could be recruited in the absence of glutamatergic inputs from primary afferents. The release of neuropeptides from capsaicin-sensitive C-primary afferents may activate GABAergic and glycinergic interneurons in superficial laminae, and the inhibitory activity may be further forwarded to lamina V neurons. The capsaicin-sensitive inhibitory pathway may play an important role in the control of nociceptive transmission in the spinal cord.

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Power AE, Thal LJ, McGaugh JL (2001) Memory enhancement induced by post-training norepinephrine in the basolateral amygdala is blocked by 192-IgG saporin lesions of the nucleus basalis magnocellularis. Neuroscience 2001 Abstracts 84.13. Society for Neuroscience, San Diego, CA.

Summary: Drugs and stress hormones act in the basolateral amygdala (BLA) to modulate memory storage. The BLA projects to the nucleus basalis magnocellaris (NBM), which sends broad cholinergic projections to the neocortex. These NBM-cortex projections have been implicated in learning, memory storage and cortical plasticity. The current study was designed to test whether the cholingeric NBM-cortex projections are involved in BLA-mediated memory modulation. Rats were given bilateral cholinergic lesions of the NBM with 192-IgG saporin (0.1 μg/ 0.5 μl per side) or sham infusions, and implanted with bilateral cannulae aimed at the BLA. One week after surgery the rats were trained in the inhibitory avoidance task. Immediately after training, the rats were given bilateral infusions of norepinephrine (0.3μg, 1.0 μg, or 3.0 μg) or vehicle (0.2 μl PBS) into the BLA. On a 48-h retention test, the norepinephrine infusions produced a dose-dependent enhancement of retention (0.3μg and 1.0 μg doses) in sham-operated controls. NBM-lesioned rats that received these memory-enhancing doses of norepinephrine had retention latencies that did not differ from vehicle infused controls. Thus memory enhancement induced by post-training intra-BLA infusion of norepinephrine was blocked in 192-IgG saporin NBM-lesioned rats. ChAT assays of frontal and occipital cortices confirmed the lesions. These findings indicate that the cholinergic NBM-cortex projections are involved in BLA-mediated modulation of memory.

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Nakatsuka T, Takeda D, Gu JG (2001) α,β-methylene ATP sensitive P2X receptor mediated enhancement of glutamate release from the central terminals of Aδ primary afferents onto lamina V neurons in rat spinal cord. Neuroscience 2001 Abstracts 158.16. Society for Neuroscience, San Diego, CA.

Summary: We examined the role of αβmATP-sensitive P2X receptors in modulating glutamate release from sensory synapses of the spinal cord by using whole-cell patch-clamp recordings from dorsal horn neurons in lamina V region. The majority of lamina V neurons synapsed with terminals expressing αβmATP-sensitive P2X receptors. Application of P2X receptor agonist 100 μM αβmATP resulted in a large increase in mEPSC frequency. The increases in mEPSC frequency by αβmATP were completely abolished by the P2X receptor antagonist 10 μM PPADS, but were not blocked by Ca2+ channel blocker 30 μM La3+. αβmATP remained to be effective in increasing mEPSC frequency after the removal of superficial dorsal horn (lamina I-III) or after the injection of IB4-saporin into sciatic nerve to remove P2X3 expressing afferent terminals. Furthermore, we found that αβmATP-sensitive synapses of lamina V neurons were associated with central terminals derived from Aδ primary afferents. The EPSCs evoked by dorsal root stimulation at Aδ-fiber intensity were potentiated by 1 μM αβmATP as well as by the ecto-ATPase inhibitor 10 μM ARL67156, and depressed in the presence of 10 μM PPADS and 5 μM suramin. These results suggest that αβmATP-sensitive P2X receptors play a significant role in modulating excitatory synaptic transmission in the spinal cord.

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Bailey AM, Rudisill ML, Hoof EM, Loving ML (2001) The effects of 192 IgG-saporin lesions to the nucleus basalis magnocellularis/substantia innominata (nBM/SI) on two learning set formation tasks and open field activity. Neuroscience 2001 Abstracts 85.13. Society for Neuroscience, San Diego, CA.

Summary: Male Long Evans rats (Rattus norvegicus) were used to investigate the role of the nucleus basalis magnocellularis/substantia innominata (nBM/SI) in learning set formation. Rats with bilateral 192 IgG-Saporin lesions to the nBM/SI were tested on olfactory discrimination learning set, discrimination reversal learning set, and open field activity. Assessment of open field activity indicated no group differences in general activity levels. Control animals performed significantly better than chance on trial 2 across the 50 problems given in the olfactory discrimination learning set paradigm, suggesting evidence of learning set formation. The nBM/SI lesion group did not perform significantly above chance on trial 2 overall; however, they did perform above chance on trial 2 over the last 10 problems in the olfactory discrimination learning set task. Discrimination reversal followed testing on the olfactory discrimination learning set task. No group differences were seen in discrimination reversal performance. Both control and nBM/SI lesioned animals performed well on the discrimination reversal learning set task, improving with each reversal, and both groups performed significantly higher than expected by chance on trial 2 in the discrimination reversal paradigm, indicating learning set formation. Results suggest that removal of the nBM/SI cholinergic system through 192 IgG-Saporin lesions impairs early acquisition of learning set compared to control animals, but does not interrupt later use of learning set formation.

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Stahl CE, Kusayama T, Keep M, Elmer E, Watanabe S, Borlongan CV (2001) Cyclosporine-A improves performance in passive avoidance task in adult rats with basal forebrain lesions. Neuroscience 2001 Abstracts 101.11. Society for Neuroscience, San Diego, CA.

Summary: While mainly used as an immunosuppressant, newly identified properties of CsA suggest its potential as a therapeutic agent for neurological disorders. In the present study, we investigated the effects of CsA in acquisition and retention of passive avoidance task in adult rats lesioned with 192-IgG-saporin, an immunotoxin that targets cholinergic neurons in the basal forebrain. Starting on the day of the lesion up to 7 days thereafter, animals received either daily CsA (10 mg/kg, i.p. ) or vehicle alone. On day 8 (acquisition), animals were trained in a three-compartment shuttle box passive avoidance task. Twenty-fours later, the retention tests were performed. During the acquisition phase, animals that received CsA treatment significantly entered less in the shock-associated box than those that received vehicle alone. However, the mean total acquisition times between the two groups were not statistically significant. In the retention phase, CsA-treated animals displayed significantly longer latency to stay in the safe compartment compared to vehicle-treated animals. Histological analysis using ChAT immunostaining revealed sparing (80% of control) of basal forebrain cholinergic neurons in CsA-treated animals. The use of CsA may prove beneficial for treatment of neurological disorders characterized by a dysfunctional cholinergic system.

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Works SJ, Wellman CL (2001) Differential dendritic atrophy in frontal cortex after cholinergic lesion in young adult and aged rats. Neuroscience 2001 Abstracts 101.17. Society for Neuroscience, San Diego, CA.

Summary: Previously, we demonstrated that plasticity of frontal cortex is altered in aging rats: three months after surgery, ibotenic acid lesions of the nucleus basalis magnocellularis (NBM) produce larger declines in dendritic morphology in frontal cortex of aged rats relative to young adults. To determine whether the differential effect of the lesion was due specifically to loss of cholinergic input from the NBM, we assessed dendritic morphology in frontal cortex after cholinergic depletion in young adult and aged male rats. Rats received unilateral lesions of the NBM using 192 IgG-saporin, and sham lesions of the contralateral NBM. Two weeks after surgery, brains were stained using a Golgi-Cox procedure. Pyramidal neurons in lamina II-III of frontal cortex were drawn and dendritic morphology was quantified in three dimensions. In young adults, lesions did not alter overall branch number or length. However, in aged rats, lesions decreased basilar dendritic number and length, by 17% and 25% respectively. Furthermore, young adults demonstrated a lesion-induced redistribution of basilar dendrites: dendritic material proximal to the soma was decreased 15%, while distal dendritic material was increased as much as threefold relative to the sham-lesioned hemisphere. Alternatively, lesions in aged rats decreased the amount of distal dendritic material by 25%. Thus, the dendritic atrophy resulting from NBM lesions in aged rats occurs within two weeks after lesion, and results specifically from loss of cholinergic innervation.

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