References

Cortez AM, Amodeo D, Chavez C, Flesher M, Balbous M, Butt AE (2006) Selective 192 IgG-saporin lesions of the cholinergic basal forebrain impair negative patterning discrimination learning in rats. Neuroscience 2006 Abstracts 162.7. Society for Neuroscience, Atlanta, GA.

Summary: We have previously argued that the cholinergic nucleus basalis magnocellularis (NBM) is necessary for complex or “configural” association learning, but is not necessary for simple association learning. The current experiment further tests the hypothesis that the cholinergic basal forebrain is involved in configural association learning by examining the respective contributions of the NBM projections to neocortex and the medial septal (MS) projections to hippocampus in separate groups of rats. Rats with bilateral 192 IgG-saporin lesions of either the NBM or MS were tested in a negative patterning operant discrimination task. Rats were food-reinforced (+) for responding in the presence of a light (L+) or a tone (T+), but were not reinforced (-) for responding in the presence of the configural stimulus comprised of the light and tone presented simultaneously (LT-). We have previously shown that NBM lesions cause a transient but significant impairment in negative patterning discrimination learning. Consequently, we hypothesized a similar NBM lesion-induced impairment in the current experiment. Because hippocampus lesions cause dramatic disruptions in the acquisition of the negative patterning task, it was hypothesized that lesions of the cholinergic neurons of the MS would cause a greater degree of impairment than NBM lesions. Consistent with our hypotheses, NBM lesions retarded but did not prevent acquisition. MS lesions, in contrast, caused significantly greater impairments than NBM lesions. Rats in both lesion groups responded normally to L+ and T+ but responded more often to LT-. These findings demonstrate intact simple association learning but disrupted configural association following damage to the cholinergic neurons of the NBM or MS. Results suggest that cholinergic basal forebrain modulation of neocortex and hippocampus contributes to configural association learning.

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

Abitoye PA, Li P, Gibbs RB, Johnson DA (2006) Steroid sulfatase inhibitor (p-O-sulfamoyl) – tetradecanoyl tyramine (du-14) enhances memory retention in rats with cholinergic lesion. Neuroscience 2006 Abstracts 163.15. Society for Neuroscience, Atlanta, GA.

Summary: Previous studies have shown that altering the metabolism of neurosteroids via inhibition of steroid sulfatase (SSI) would reverse scopolamine induced amnesia. In this study we tested whether the SSI, DU-14 could enhance memory retention of foot shock in rats with a selective lesion of cholinergic neurons projecting from the medial septum to the hippocampus using a passive avoidance paradigm. Male Sprague-Dawley rats were infused with either 0.2 μg of 192 IgG-saporin (SAP), a selective cholinergic immunotoxin, or artificial cerebrospinal fluid (CSF) into the medial septum. One week later, the animals were placed into a passive avoidance apparatus and administered footshock trials (1 mA / 1 sec) until criterion (2 consecutive trials with a crossover latency of at least 5 min). On the next day, rats from SAP and CSF groups were then randomly assigned to receive DU-14 (30mg / kg) or corn oil (vehicle) daily for 6 days. Rats were tested for memory retention three hours after the last day dosing. DU-14 increased crossover latency by 74.5% in the CSF control group and 54.8% in SAP treated animals. In order to determine whether DU-14 or SAP treatment inhibited locomotor activity independent of memory, other animals were dosed with vehicle or DU-14 and crossover latency was tested before acquisition of footshock. There were no significant differences between treatment groups. These results suggest that steroid sulfatase inhibition may enhance memory retention in rats with hippocampal cholinergic lesion.

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

Rivat C, Vera-Portocarrero LP, Ibrahim MM, Mata HP, Stagg NJ, De Felice M, Porreca F, Malan TP (2006) Ascending and descending pathways support fentanyl-induced pain hypersensitivity with and without a surgical incision. Neuroscience 2006 Abstracts 248.10. Society for Neuroscience, Atlanta, GA.

Summary: Acutely administered the analgesic opioid fentanyl has been shown to enhance mechanical hypersensitivity in a model of surgical pain induced by hindpaw incision in the rat. Recent evidence showed the importance of descending pathways originating from the rostral ventromedial medulla (RVM) in opioid-induced hyperalgesia after sustained morphine administration. Such hyperalgesia is also associated with numerous neurochemical changes in primary afferent fibers and spinal dorsal horn, such as increased spinal dynorphin expression. These changes may activate ascending pathways, mediated in part by NK-1 neurotransmission. Here, we examined the roles of ascending and descending pathways in sensory hypersensitivity after acute fentanyl administration. Male Sprague-Dawley rats received 4 fentanyl (4×100 μg/kg, s.c.) or saline injections administered at 15 min intervals. Some animals also received an incision in the plantar hindpaw. Thermal hyperalgesia and tactile allodynia were measured daily. In control rats, fentanyl induced analgesia followed by an immediate and long-lasting hyperalgesia, as previously described. Fentanyl also enhanced pain sensitivity induced by plantar incision. In SP-saporin pretreated rats, fentanyl induced analgesia and a moderate long-lasting hyperalgesia. The SP-saporin pretreatment slightly reduced both hyperalgesia and allodynia in postoperative rats and, to a larger extent, in fentanyl treated rats. Lidocaine injection in the RVM completely reversed fentanyl-induced sensory hypersensitivity and fentanyl enhancement of incision-induced hyperalgesia and allodynia. A slight reduction of incision-induced sensory hypersensitivity was observed after lidocaine injection in rats without fentanyl pretreatment. Spinal dynorphin content increased by 30 ± 7% and 71 ± 33% in fentanyl and fentanyl/incision treated rats, respectively. These data support the crucial role of the descending pathways from the RVM in the fentanyl-induced hyperalgesia and the partial implication of the NK-1 receptor containing ascending pathways.

Related Products: SP-SAP (Cat. #IT-07)

Hayashida K, Clayton B, Ma W, Eisenach J (2006) Brain-derived neurotrophic growth factor from p75-expressing sensory afferents drives spinal noradrenergic fiber sprouting following nerve injury in rats. Neuroscience 2006 Abstracts 248.19. Society for Neuroscience, Atlanta, GA.

Summary: We previously showed that peripheral nerve injury in mice results in sprouting of noradrenergic (NA) fibers in the spinal cord, possibly reflecting a substrate for increased efficacy of α2-adrenoceptor agonists such as clonidine. Here we tested whether spinal NA fiber sprouting also occurs in rats after peripheral nerve injury and examined the role of brain derived neurotrophic factor (BDNF) for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in mechanical hypersensitivity of the paw ipsilateral to injury and sprouting of NA fibers in the dorsal horn of the lumbar spinal cord. BDNF content increased in L4-L6 dorsal root ganglia (DRG) ipsilateral to injury and in lumbar spinal cord following nerve injury and intrathecal infusion of BDNF antiserum prevented spinal NA sprouting. Pro-BDNF immunoreactivity increased in L4-L6 DRG neurons ipsilateral to injury, especially in large-size neurons, and was highly co-localized with the low affinity neurotrophin receptor, p75NTR. Intrathecal injection of anti-p75NTR linked to saporin destroyed p75NTR expressing afferents and reversed NA sprouting after nerve injury. Manipulations which blocked NA sprouting (BDNF antiserum, anti-p-75NTR saporin) also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. These results suggest that increased BDNF synthesis and release from p75NTR expressing injured and uninjured sensory afferents drives spinal NA sprouting following nerve injury and this sprouting increase the capacity for analgesia from drugs which utilize the NA pathway.

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

Tait DS, Brown VJ, Farovik A, Theobald DE, Dalley JW, Robbins TW (2006) Lesions of the dorsal noradrenergic bundle impair attentional set-shifting in the rat. Neuroscience 2006 Abstracts 264.4. Society for Neuroscience, Atlanta, GA.

Summary: Rats with medial prefrontal cortex (mPFC) lesions are impaired in attentional set shifting (Birrell and Brown, 2000, J Nsci, 20:4320-4324). The mPFC receives multiple projections, but norepinephrine (NE) has previously been reported to modulate attention by its action in the mPFC (for review see Dalley et al., 2004, Nsci Biobeh Rev, 28:771-784), including shifting attentional set. Indeed, there is recent evidence that increasing NE in the mPFC by autoreceptor antagonism improves set-shifting performance in rats (Lapiz and Morilak, 2006, Nsci, 137:1039-1049). Furthermore, reduction of prefrontal NE by infusion of anti-DBH-saporin into PFC has been shown to impair attentional set-shifting in rats (Eichenbaum et al., 2003, SfN Abstract 940.7). The main source of noradrenergic input to the mPFC is from locus coerulus via the dorsal noradrenergic bundle (DNAB). This study examined the effect of lesions of the DNAB on the acquisition, maintenance and shifting of attentional set. Eleven male Lister-hooded rats received bilateral DNAB lesions by infusion of 6-hydroxydopamine (4μg in 2μl each side) at (nosebar -2.4mm) AP -6.0mm, ML ±1.0mm, DV -5.0mm (from dura). Twelve control rats received injections of vehicle. Rats learned to dig for bait in bowls then learned two simple discriminations – based on the bowls odor or the digging substrate – to a criterion of six consecutive correct trials. The next day, a series of discriminations tested acquisition of novel discriminations (both intra (ID) and extradimensional (ED)) and reversal learning. Trials to criterion, incorrect trials and dig-latencies were recorded and analysed. At conclusion of testing, brain tissue samples were analysed for NE content by HPLC-ECD. All rats required more trials to reverse previously learned associations, and to learn new discriminations when attentional refocusing was required (ED shift). Rats with DNAB lesions were unimpaired at reversal stages, but were impaired at the ED acquisition stage. Lesioned rats showed reductions of NE levels in mPFC (up to 95% in the infralimbic region, 89% in the prelimbic region and 93% in cingulate area Cg1). These data provide further evidence for the role of NE in attentional set-shifting, and combine with previous data to elucidate the mechanisms by which mPFC mediates attentional set-shifting in the rat.

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

Chauhan NB (2006) Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain. Neuroscience 2006 Abstracts 271.8. Society for Neuroscience, Atlanta, GA.

Summary: Today’s Alzheimer’s disease (AD) research lacks a “complete” model that would represent both plaque and tangle pathology together with correlative memory deficits. Although currently developed transgenic model including APP/PS1/tau mutations do not “truly” represent AD because tangles observed in AD brain are independent of tau mutations. Subtly increased β-amyloid (Aβ) levels either due to familial mutations or sporadic causes, primarily targets pre-tangle cytopathology and degeneration of basal forebrain cholinergic neurons (BFCN) via deranged signaling of glygogen synthase kinase 3-beta (GSK3β)-, protein kinase A (PKA)-, and extracellular signal-regulated kinase (ERK2) of ERK-mitogen-activated protein kinase (MAPK) cascade, leading to reduced phosphorylation of cAMP responsive element binding protein (CREB) that results in synaptic and memory deficits much earlier than the emergence of classic AD-pathology. Thus, subtly elevated Aβ, together with BFCN deficits resulting from Aβ-induced deranged signaling, set up a vicious feedback loop to produce characteristic plaque- and tangle-pathology observed in AD. Based on these facts, we wished to test if selective lesioning of basal fore brain cholinergic neurons during the early stages of amyloid build-up will exacerbate tau phosphorylation and produce tangle-like inclusions in transgenic mice with APP mutations. We produced selective immunotoxic lesions of BFCN by injecting the BFCN-specific cholinergic immunotoxin, which is known to specifically target p75-expressing BFCN and spare p75-expressing cerebellar neurons (Mu-p75-Saporin, Advanced Targeting Systems, #IT-16), intracerebroventricularly (ICV) in TgCRND8 mice harboring Swedish (KM670/671NL) and Indiana (V717F) mutations. This model exhibited tangle-like inclusions, provoked already existing plaque pathology, and worsened already impaired behavioral deficits.

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Keener WK, Rivera VR, Young CC, Poli MA (2006) An activity-dependent assay for ricin and related RNA N-glycosidases based on electrochemiluminescence. Anal Biochem 357(2):200-207. doi: 10.1016/j.ab.2006.07.005

Summary: The authors use synthetic biotinylated RNA substrates to assay adenine-specific RNA N-glycosidases, one of which is saporin (Cat. #PR-01). The RNA substrates are annealed to a ruthenylated oligodeoxynucleotide, allowing the capture of ruthenium chelate on magnetic beads. The N-glycosidase activity can then be detected by enzyme-linked chemiluminescence. The developed assay provides a robust method for assessing threats involving N-glycosidases.

Related Products: Saporin (Cat. #PR-01)

Masawaki A, Sugiyo S, Shimoda T, Sakai Y, Watanabe M, Moritani M, Yoshida A, Niwa H, Takemura M (2006) Formalin-induced pain-related responses in rat lacking neurokinin-1 receptor neurons in the trigeminal nucleus caudalis. Neuroscience 2006 Abstracts 50.8. Society for Neuroscience, Atlanta, GA.

Summary: This study examines the effect of intra cisterna magna injection of substance P (SP) conjugated to saporin (SP-Sap; 5µM, 5µl) on formalin-induced pain-related behavior (PRB; face scrubbing behavior ) and c-Fos expression in the trigeminal nucleus caudalis (SpVc). In SP-Sap-treated rats, the numbers of NK-1-immunoreactive neurons in lamina I of the SpVc decreased compared with those in saline- or blank Sap-treated rats. The mean numbers ±SEM of PRB /5 min at the first phase (0-5 min after For injection) were 58.2±19.2 in the SP-Sap-treated rats, 115.6±14.0 in the saline treated rats and 86.9±45.7 in the blank-Sap-treated rats. The numbers at the quiescent period (5-10 min) were 45.2±26.3 in the SP-Sap- treated rats, 93.6±26.5 in the saline treated rats and 69.4±16.3 in the blank-Sap-treated rats. These at the former second phase (10-50 min) were 58.1±22.3 in the SP-Sap-treated rats, 133.6±26.1 in the saline treated rats and 95.8±29.6in the blank-Sap-treated rats. These at the latter second phase (55-90 min) were 7.0±5.6 in the SP-Sap-treated rats,13.7±12.4 in the saline treated rats and 10.4±22.5 in the blank-Sap-treated rats. These results indicate that formalin-induced nociceptive responses in the SP-Sap-treated rats are reduced.

Related Products: SP-SAP (Cat. #IT-07), Blank-SAP (Cat. #IT-21)

Martin MM, Schultz MD, Winter SS, Wallace DG (2006) Selective cholinergic lesions of the medial septum disrupt dead reckoning-based navigation. Neuroscience 2006 Abstracts 66.10. Society for Neuroscience, Atlanta, GA.

Summary: Recent investigations using selective lesion techniques have suggested that the septohippocampal cholinergic system may not be critical for spatial orientation. These studies employ spatial tasks that provide the animal with access to both allothetic and idiothetic cues; therefore, the spared performance may reflect intact spatial orientation or compensatory mechanisms associated with one class of spatial cues. The present study examined the contribution of the septohippocampal cholinergic system to spatial behavior by examining performance in foraging tasks in which cue availability was manipulated. Female Long-Evans rats were either given a sham surgery or a selective medial septum/ vertical limb of the diagonal band cholinergic lesion using the neurotoxin 192 IgG-saporin. Rats were then trained to find food pellets randomly located on an open field which they then carried back to a visible home base (“cued”) to eat. Once they became proficient at returning to their home base location, cued training was alternated with probes. The three probes included 1) replacing the visible home base with a hidden home base to measure ability to use cues not associated with the home base (“uncued”); 2) moving the hidden home base to a new location to pit use of allothetic cues against idiothetic cues (“reversal”); and 3) testing under completely dark conditions thereby limiting access only to idiothetic cues (“dark”). Although both groups could use allothetic cues as evidenced by intact performance on cued and uncued probes, rats with compromised septohippocampal cholinergic systems were impaired during the reversal and dark probes. These observations are consistent with a selective role for the septohippocampal cholinergic system in idiothetic cue processing necessary for dead reckoning based navigation.

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

Bugarith K, Dinh TT, Li AJ, Speth RC, Ritter S (2006) Featured Article: Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake. Targeting Trends 7(4)

Related Products: Anti-DBH-SAP (Cat. #IT-03), NPY-SAP (Cat. #IT-28), Saporin (Cat. #PR-01), Blank-SAP (Cat. #IT-21)

Read the featured article in Targeting Trends.

See Also:

• Bugarith K et al. Basomedial hypothalamic injections of neuropeptide Y conjugated to saporin selectively disrupt hypothalamic controls of food intake. Endocrinology 146(3):1179-1191, 2005.