Targeting Topics 12q4

Control of sleep and wakefulness.

Brown RE, Basheer R, McKenna JT, Strecker RE, McCarley RW.

Physiol Rev 92(3):1087-1187, 2012.

This review summarizes mechanisms in the brain that control sleep and wakefulness. Areas discussed include wakefulness promoting systems, non-REM sleep and REM sleep definitions, the function of each kind of sleep, and dysfunction that occurs as a result of sleep disruption. Several targeted conjugates are mentioned, such as 192-IgG-SAP (Cat. #IT-01), anti-DBH-SAP (Cat. #IT-03), and orexin-SAP (Cat. #IT-20). The review summarizes the use of these products to better understand sleep networks.

Time to pay attention: attentional performance time-stamped prefrontal cholinergic activation, diurnality, and performance.

Paolone G, Lee TM, Sarter M.

J Neurosci 32(35):12115-12128, 2012.

This work examined the role that neuronal mechanisms have in cognitive performance on a fixed-time task. The authors performed bilateral 160 ng infusions of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis and substantia innominata of the basal forebrain of rats that had reached stable performance on a sustained attention task. In control animals trained in the same task, prefrontal cholinergic neurotransmission persisted at the fixed time even after the task was terminated. Both lesioning and altering the task training time impaired task performance.

A nociceptive signaling role for neuromedin B.

Mishra SK, Holzman S, Hoon MA.

J Neurosci 32(25):8686-8695, 2012.

Previous work suggests that neuromedin B (NMB) is involved in nociception. Direct injection of the peptide causes nociceptive sensitization, while NMB antagonists attenuate sensitization in reponse to nerve stimulation with mustard oil. Specific subsets of dorsal horn interneurons were eliminated by administering either 10 μg of the custom conjugate neuromedin B-SAP, 0.13 μg of SSP-SAP (Cat. #IT-11), or 1.3 μg of bombesin-SAP (Cat. #IT-40). Blank-SAP (Cat. #IT-21) was used as a control. The data indicate that NMB may be involved in the perception of thermal sensation, but not mechanical or pruritic sensation.

PET imaging of cholinergic deficits in rats using [(18)F]fluoroethoxybenzovesamicol ([(18)F]FEOBV).

Parent M, Bedard MA, Aliaga A, Soucy JP, Landry St-Pierre E, Cyr M, Kostikov A, Schirrmacher E, Massarweh G, Rosa-Neto P.

Neuroimage 62(1):555-561, 2012.

In order to better understand and evaluate neurodegenerative diseases imaging agents are necessary to visualize the affected systems. [18F]fluoroethoxybenzovesamicol ([18F]FEOBV) is one such agent that shows promise for labeling the vesicular acetylcholine transporter with positron emission tomography. The authors injected 0.2 μg of 192-IgG-SAP (Cat. #IT-01) into the left hemisphere of rats to model cholinergic terminal loss as seen in aged animals. Loss of these terminals was found to reduce [18F]FEOBV binding in the ventral frontal cortex on the lesioned side, and also in the homologous region of the contralateral hemisphere, allowing detection of both physiological and pathological reduction of cholinergic terminals.

Infusion of GAT1-saporin into the medial septum/vertical limb of the diagonal band disrupts self-movement cue processing and spares mnemonic function.

Koppen JR, Winter SS, Stuebing SL, Cheatwood JL, Wallace DG.

Brain Struct Funct Epub2012.

Both mnemonic and spatial processing are adversely affected by dementia due to Alzheimer’s disease. There is evidence to support the involvement of cholinergic systems in this deficit. In this work the authors examined how GABAergic neurons in the septohippocampus contribute to these cognitive functions. Rats received a total of 350 ng of GAT-1-SAP (Cat. #IT-32) infused into the medial septum-diagonal band of Broca. Although lesioned animals performed normally in tasks involving spatial cues, food hoarding was affected indicating that self-movement cue processing was interfered with by the loss of these GABAergic neurons.

Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice.

Gil-Bea FJ, Gerenu G, Aisa B, Kirazov LP, Schliebs R, Ramirez MJ.

Neurobiol Dis 48(3):439-446, 2012.

The hallmarks of Alzheimer’s disease (AD) include hippocampal cell loss, cholinergic dysfunction, amyloid plaques, and neurofibrillary tangles, among other things. This work sought to examine the interaction between cholinergic denervation, amyloid precursor protein (APP) processing, and hippocampal integrity. Tg2576 transgenic mice received 2 μg of mup75-SAP (Cat. #IT-16) injected into the third ventricle. These mice overexpress a version of human APP. Lesioned animals displayed various aspects of AD such as hippocampal synaptic pathology and neurodegeneration, indicating that immunolesions in this mouse line produce a viable model for AD.

Septohippocampal GABAergic neurons mediate the altered behaviors induced by n-methyl-D-aspartate receptor antagonists.

Ma J, Tai SK, Leung LS.

Hippocampus 22(12):2208-2218, 2012.

It is thought that the integrity of the medial septum is essential for the maintenance of hippocampal theta rhythm – and that this maintenance depends on three types of septohippocampal neurons; cholinergic, GABAergic, and glutaminergic. In this work the authors administered bilateral injections totaling 140 ng of orexin-SAP (Cat. #IT-20) into the medial septum of rats. The animals were then treated with NMDA receptor antagonists to examine the role of GABAergic neurons from the medial septum in psychotic behavior. The data suggest that septohippocampal GABAergic neurons are important for expression of psychotic symptoms caused by NMDA receptor antagonists.

Medial septal cholinergic neurons are necessary for context-place memory but not episodic-like memory.

Easton A, Fitchett AE, Eacott MJ, Baxter MG.

Hippocampus 21(9):1021-1027, 2011.

Although it is clear that neurodegenerative diseases cause memory impairment, it is uncertain to what extent cholinergic deficits cause this loss of function. The authors administered a total of 150 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum and vertical limb of the diagonal band of Broca in rats. The lesioned animals were then tested in a rodent model for human episodic memory. The rats performed well on these tests, but struggled with tests that tested the association of places with context. The results suggest that hippocampal spatial representations might not be essential for episodic memory function.

Nucleus of the Solitary Tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats.

Daubert DL, McCowan M, Erdos B, Scheuer DA.

J Physiol 590(Pt 19):4881-4895, 2012.

It has been proposed that the nucleus of the solitary tract (NTS) is highly involved in cardiovascular regulation. In light of the fact that catecholaminergic neurons in the NTS are part of stress-related neurocircuitry, the authors investigated whether these neurons attenuate blood pressure increases due to stress. Rats received 22 ng bilateral injections of anti-DBH-SAP (Cat. #IT-03) into the NTS. Mean arterial pressure and baseline plasma epinephrine were measured in a restraint test. Animals lesioned with anti-DBH-SAP displayed a significantly enhanced mean arterial pressure, and reduced plasma epinephrine. These data suggest that catecholaminergic neurons in the NTS inhibit the arterial pressure response to stress, but maintain the corticosteroid response.

CXB-909 Attenuates Cognitive Deficits in the Mu-P-75 Saporin Mouse Model of Alzheimer’s Disease.

Lowrance S, Matchynski J, Rossignol J, Dekorver N, Sandstrom M, Dunbar G.

Neuroscience & Medicine 3(1):65-68, 2012.

CXB-909 is a small molecule NGF amplifier that has been shown to enhance neurite outgrowth in various neuronal cell lines. This type of molecule has potential therapeutic use in disorders such as Alzheimer’s disease. In this work the authors lesioned cholinergic cells in the basal forebrain of mice with bilateral 0.8 μg intracerebroventricular injections of mup75-SAP (Cat. #IT-16). Lesioned animals performed significantly worse than controls in a water maze task. Lesioned animals subsequently treated with CXB-909 displayed improved performance, indicating that CXB-909 can attenuate memory deficits caused by loss of cholinergic input.

Cholinergic depletion in nucleus accumbens impairs mesocortical dopamine activation and cognitive function in rats.

Laplante F, Zhang ZW, Huppe-Gourgues F, Dufresne MM, Vaucher E, Sullivan RM.

Neuropharmacology 63(6):1075-1084, 2012.

Current thought is that loss of cholinergic function in the nucleus accumbens (N.Acc) is associated with schizophrenia. This deficit is accompanied by low dopaminergic activity in the prefrontal area, which adversely affects working memory. Rats received bilateral injections totaling 500 ng of anti-ChAT-SAP (Cat. #IT-42) into the N.Acc; rabbit IgG-SAP (Cat. #IT-35) was used as a control. Lesioned animals had markedly reduced mesocortical dopamine activation, which corresponded with cognitive impairments. The data suggest that loss of cholinergic neurons in the N.Acc causes loss of dopamine function in the mesocorticolimbic system.

A2 noradrenergic lesions prevent renal sympathoinhibition induced by hypernatremia in rats.

Pedrino GR, Freiria-Oliveira AH, Almeida Colombari DS, Rosa DA, Cravo SL.

PLoS One 7(5):e37587, 2012.

It is thought that renal sympathetic nerve activity is a key component of the response to acute or chronic elevated concentrations of saline in the blood stream. The authors investigated what neurons are involved in the central control of these responses. Rats received bilateral 6.3 ng injections of anti-DBH-SAP (Cat. #IT-03) into the nucleus of the solitary tract. An equimolar amount (1.3 ng) of saporin (Cat. #PR-01) was used as a control. Loss of the A2 noradrenergic neurons altered the renal sympathetic nerve activity response to elevated saline, suggesting that these neurons help regulate the extracellular fluid compartment.

Chronic treadmill exercise in rats delicately alters the Purkinje cell structure to improve motor performance and toxin resistance in the cerebellum.

Huang TY, Lin LS, Cho KC, Chen SJ, Kuo YM, Yu L, Wu FS, Chuang JI, Chen HI, Jen CJ.

J Appl Physiol 113(6):889-895, 2012.

It is known that exercise can improve motor performance, but the cellular changes that occur in the cerebellum in response to exercise are not understood. Rats were subject to exercise training and a rotarod test was used to evaluate performance. After training some animals were given a 2 μg injection of OX7-SAP (Cat. #IT-02) into the lateral ventricle. In sedentary rats OX7-SAP administration reduced rotarod performance as well as eliminated 60% of Purkinjie cells. Rats given exercise training exhibited much milder injury in the cerebellum as a result of the lesion and maintained a higher level of rotarod performance than the sedentary group.

Local serotonin mediates cyclic strain-induced phenotype transformation, matrix degradation, and glycosaminoglycan synthesis in cultured sheep mitral valves.

Lacerda CM, Kisiday J, Johnson B, Orton EC.

Am J Physiol Heart Circ Physiol 302(10):H1983-90, 2012.

Calcific aortic valve disease and myxomatous mitral valve disease (MMVD) are the most commonly seen degenerative heart valve diseases. Exogenous serotonin has been shown to induce valvulopathy, but current opinion regards serotoninergic and degenerative valvulopathies as unrelated. This work investigated the relationship between serotonin synthesis and strain-induced MMVD in cultured sheep mitral valve leaflets. Anti-SERT (Cat. #AB-N09) was used in immunoblotting experiments. The results demonstrate local serotonin synthesis by mitral valves, modulation of this synthesis by tensile loading, and inhibition of serotonin results in the reduction of strain-mediated protein expression.

Lamina I NK1 expressing projection neurones are functional in early postnatal rats and contribute to the setting up of adult mechanical sensory thresholds.

Man SH, Geranton SM, Hunt SP.

Mol Pain 8(1):35, 2012.

Projections from lamina I neurons regulate mechanical and thermal sensitivity due to injury. Little is known about how these pathways develop immediately after birth. Rats at postnatal day 3 were treated with 2 μl of 5 μM SP-SAP (Cat. #IT-07) injected into the intrathecal space. Blank-SAP (Cat. #IT-21) was used as a control. The data show that neurokinin-1 positive neurons project to the parabrachial nucleus in the hindbrain, and that these neurons and lamina I neurons were responsive to noxious stimulation at postnatal day 3. Treated animals also displayed increased mechanical sensitivity from postnatal day 45 on.

Leptin-sensitive neurons in the arcuate nuclei contribute to endogenous feeding rhythms.

Li AJ, Wiater MF, Oostrom MT, Smith BR, Wang Q, Dinh TT, Roberts BL, Jansen HT, Ritter S.

Am J Physiol Regul Integr Comp Physiol 302(11):R1313-26, 2012.

It is clear that the arcuate nucleus (Arc) plays an important role in the generation of feeding rhythms. To clarify how this region modulates signals governing food intake the authors took advantage of the Arc mediation of leptin. Rats received bilateral injections of leptin-SAP (Cat. #IT-47, 56.5 ng per dose) into each Arc. Blank-SAP (Cat. #IT-21) was used as a control. The lesioned animals quickly became obese and displayed arrhythmic eating patterns under normal light conditions. The results indicate that lesioned neurons in the Arc as well as those in the suprachiasmatic nuclei are required for maintenance of feeding rhythms controlled by photic cues.

Intrinsic voltage dynamics govern the diversity of spontaneous firing profiles in basal forebrain noncholinergic neurons.

Ovsepian SV, Dolly JO, Zaborszky L.

J Neurophysiol 108(2):406-418, 2012.

The voltage modulation functions of the basal forebrain have commonly been associated with cholinergic cells. More recent work has suggested that noncholinergic cells have an influence on this type of neuronal activity. The authors labeled cholinergic neurons by injecting 0.8-1.6 μg of Cy3-192-IgG (Cat. #FL-01) into the lateral ventricles of rats. Patch-clamp recordings were taken from brain slices of these animals under various blockade conditions. The results demonstrate that neuropeptide Y receptors as well as ions such as Ca2+ and K+ are important for regenerative firing in basal forebrain cholinergic neurons.

Intact Catecholamine Inputs to the Forebrain Are Required for Appropriate Regulation of CRH and Vasopressin Gene Expression by Corticosterone in the Rat Paraventricular Nucleus.

Kaminski KL, Watts AG.

J Neuroendocrinol 24(12):1517-1526, 2012.

Corticosterone releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVH) control release of adrenocorticotropic hormone and glucocorticoids. In order to determine the contribution of these neurons to CRH and vasopressin expression in the PVH the authors administered bilateral 42 ng injections of anti-DBH-SAP (Cat. #IT-03) into the PVH of both normal and adrenalectomized rats. Mouse IgG-SAP (Cat. #IT-18) was used as a control. The data demonstrate that under certain conditions CRH and vasopressin gene expression is modulated by interactions between corticosterone and catecholaminergic projections to the hypothalamus.

Neonatal cholinergic lesion alters the acoustic structure of infant rat vocalization but not the early cognitive development.

Kruger HS, Hanganu-Opatz IL.

Dev Psychobiol 55(3):294-308, 2013.

The architecture of the cerebral cortex is dependent on cholinergic innervations for proper maturation and network assembly. The authors administered 0.1 μg of 192-IgG-SAP (Cat. #IT-01) to each lateral ventricle of rats on the day of birth. Although the resulting cholinergic depletion did not affect the general development of the rats during the first two weeks of life, infant ultrasonic vocalization was significantly affected. The altered vocalization did not affect maternal care of the pup, suggesting that previous results recording behavioral deficits in the pups after basal forebrain lesions were due to cholinergic depletion rather than altered mother-pup interaction.