Targeting Topics 16q2

The peptidergic control circuit for sighing.

Li P, Janczewski WA, Yackle K, Kam K, Pagliardini S, Krasnow MA, Feldman JL.

Nature 530(7590):293-297, 2016. PMID: 26855425

Sighs are often associated with relief or sadness, but rodents sigh spontaneously dozens of times per hour. There are physiological benefits to sighing, including enhancement of gas exchange and preservation of lung integrity. The authors identify a peptidergic sigh control circuit in the retrotrapezoid nucleus/parafacial respiratory group of the mouse brain that projects to the pre-Bötzinger complex. Mice received bilateral 6.2-ng injections of Bombesin-SAP (Cat. #IT-40) into the pre-Bötzinger complex. Blank-SAP (Cat. #IT-21) was used as control. Elimination of the bombesin receptor-expressing neurons or inhibition of neuromedin B receptor-expressing neurons suppressed sighing. Interfering with the activity of both receptors abolished sigh activity while leaving normal breathing intact. The data suggest that overlapping peptidergic pathways are the core of a sigh control circuit. (See article on Pg 2).

Pain sensitivity following loss of cholinergic basal forebrain (CBF) neurons in the rat.

Vierck CJ, Yezierski RP, Wiley RG.

Neuroscience 319:23-34, 2016. PMID: 26812034

There is a large amount of research on the involvement of cholinergic mechanisms on spinal transmission of pain signals, indicating that cholinergic agonists can attenuate this kind of pain. In contrast, some studies have shown affective reactions to pain are suppressed by cholinergic antagonists. The authors investigated the disagreement between reflexive and affective reactions with a 4-μg 192-IgG-SAP (Cat. #IT-01) injection into the left lateral ventricle of rats. Animals were tested in temperature escape and sound stress models. Lesioned rats displayed decreased escape from thermal stimulation, as well as loss of the normal hyperalgesic effect of sound stress. Results indicate that the basal forebrain cholinergic system plays a role in central processing of pain. (See Pg 1.)

Ablation of mu opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors.

Fu R, Chen X, Zuo W, Li J, Kang S, Zhou LH, Siegel A, Bekker A, Ye JH.

Neuropharmacology 107:58-67, 2016. PMID: 26921770

In this work the authors investigated cellular mechanisms underlying the aversive effects of alcohol that limit its intake. Previous work has linked synaptic inhibition of dopamine neurons in the ventral tegmental area to this aversion. Rats conditioned to ingest ethanol received bilateral injections totaling 3 pmol of Dermorphin-SAP (Cat. #IT-12) into the rostromedial tegemental nucleus (RTMg). Blank-SAP (Cat. #IT-21) was used as a control. Lesioned animals displayed significantly increased preference for, and intake of ethanol, while showing no change in the desire for sucrose. The results indicate that mu opioid expressing GABAergic neurons in the RTMg are highly involved in the regulation of ethanol consumption.

Substituting mouse transcription factor Pou4f2 with a sea urchin orthologue restores retinal ganglion cell development.

Mao CA, Agca C, Mocko-Strand JA, Wang J, Ullrich-Lüter E, Pan P, Wang SW, Arnone MI, Frishman LJ, Klein WH.

Proc R Soc B 283(1826):20152978, 2016.

Although the regulatory genes for eye development are highly conserved, there is a vision is widely diversified between species. Little is known about how gene networks vary to produce the variety of structures and functions seen across organisms. The authors investigated photoreception in echinoderms, adult sea urchins. Urchins have no structures resembling vertebrate eyes, but recent work has demonstrated the presence of photoreceptor neurons. In this work the authors transferred the urchin version of a transcription factor involved in retinal ganglion cell development into mice lacking the mouse version of that gene. The urchin gene was able to restore function in the mouse, indicating the depth of conservation for eye development gene networks. Some of the immunohistochemical staining was done with anti-melanopsin (Cat. #AB-N39) at a 1:1000 dilution.

Current and Future Issues in the development of spinal agents for the management of pain.

Yaksh TL, Fisher C, Hockman T, Wiese A.

Curr Neuropharmacol 2016. PMID: 26861470

Although conscious pain experience is driven by signals mediated supraspinally, the more high intensity pain generated by strong stimuli, tissue injury, and nerve injury is encoded at the spinal dorsal horn level. The control of pain signals at the spinal dorsal horn level is a tempting target for targeted pain therapy. This review discusses the potential targets for pain therapeutics in the spinal dorsal horn, and some of the spinal agents used to modulate pain transmission through that location. The use of SSP-SAP (Cat. #IT-11) is mentioned as a neurokinin-1 targeted molecule that can block some pain transmission.

Reorganization of Motor Cortex by Vagus Nerve Stimulation Requires Cholinergic Innervation.

Hulsey DR, Hays SA, Khodaparast N, Ruiz A, Das P, Rennaker RLn, Kilgard MP.

Brain Stimul 9(2):174-181, 2016. PMID: 26822960

Recent work has suggested that vagus nerve stimulation (VNS) can enhance neuroplasticity, and coupled with other training can drive motor cortex reorganization. These findings highlight the potential of VNS to support recovery from neurological disease. Pretrained rats received bilateral injections totaling 3.75 μg of 192-IgG-SAP (Cat. #IT-01) into the nucleus basalis (NB). Mouse-IgG-SAP (Cat. #IT-18) was used as control. Control animals displayed a substantial increase in proximal limb representation, lesion of the NB prevented this increase. Motor performance was similar between lesion and control groups, indicating that the difference in representation was not due to altered limb function.

The effect of nucleus basalis magnocellularis deep brain stimulation on memory function in a rat model of dementia.

Lee JE, Jeong da U, Lee J, Chang WS, Chang JW.

BMC Neurol 16(1):6, 2016. PMID: 26757896

Deep brain stimulation (DBS) is the application of electrical impulses to specific parts of the brain for treating disorders such as Parkinson’s disease, chronic pain, and obsessive-compulsive disorder. It has been theorized that stimulation of brain structures associated with memory can enhance cognitive function. The authors lesioned the basal forebrain of rats through bilateral injections totaling 5 μg of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricle. Animals then received DBS to the nucleus basalis magnocellularis and were tested in a Morris water maze task. Results indicate that DBS has beneficial effects on consolidation and retrieval of visuospatial memory.

Neuroplasticity and Repair in Rodent Neurotoxic Models of Spinal Motoneuron Disease.

Gulino R.

Neural Plast 2016:2769735, 2016. PMID: 26862439

TDP-43 (Transactive response DNA-binding protein) is a highly conserved nuclear protein that binds both DNA and RNA. It has been found in cytoplasmic protein aggregates of patients with conditions such as amyotrophic lateral sclerosis and Alzheimer’s disease. In this work the authors examine the role of TDP-43 in spinal cord plasticity. Mice received bilateral 3-μg injections of CTB-SAP (Cat. #IT-14) into the lateral and medial gastrocnemius muscles. The results indicate that motor performance is dependent on expression of synapsin-I, which in turn may be dependent on TDP-43.

Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer.

Nohara S, Kato K, Fujiwara D, Sakuragi N, Yanagihara K, Iwanuma Y, Kajiyama Y.

Clin Res Hepatol Gastroenterol 2016. PMID: 26774363

Scirrhous gastric cancer has the worst prognosis of gastric carcinoma, and treatment with standard cancer therapies has had minimal success. In this work the authors target CD13 as a marker for scirrhous gastric cancer. A gastric cancer cell line was challenged with a CD13 antibody coupled to Mab-ZAP (Cat. #IT-04) in an in vitro cytotoxicity assay. The anti-CD13 complex was more cytotoxic than an anti-EpCAM-immmunotoxin. These data, combined with flow cytometry analysis and enzyme activity assays, demonstrate the expression of CD13 as a marker for scirrhous gastric cancer.

Perinatal 192 IgG-Saporin as Neuroteratogen.

Petrosini L, De Bartolo P, Cutuli D, Gelfo F.

Curr Top Behav Neurosci 29:111-123, 2016. PMID: 26695170

The authors discuss the effects of perinatal administration of 192-IgG-SAP (Cat. #IT-01) and areas of research that have been investigated through the use of these lesions. The chapter covers a description of 192-IgG-SAP, lesioning methods, and outlines the short- and long-term biochemical, structural, behavioral, and cognitive effects of 192-IgG-SAP administration.

Neuroteratology and Animal Modeling of Brain Disorders.

Archer T, Kostrzewa RM.

Curr Top Behav Neurosci 29:1-40, 2016. PMID: 26857462

This work covers development and use of the neurotoxins that are most commonly used as neuroteratologic agents – producing permanent, lifelong destruction of specific groups of neurons. Saporin conjugates are discussed, in terms of animal models of human neurodegenerative, neuropsychiatric, and neurological conditions.

Locus Coeruleus and Tuberomammillary Nuclei Ablations Attenuate Hypocretin/Orexin Antagonist-Mediated REM Sleep.

Schwartz MD, Nguyen AT, Warrier DR, Palmerston JB, Thomas AM, Morairty SR, Neylan TC, Kilduff TS.

eNeuro 3(2)2016. PMID: 27022631

To examine the mechanism by which the Orexin 1r/Orexin 2r antagonist almorexant decreases wakefulness and increases NREM and REM sleep the authors utilized Anti-DBH-SAP (Cat. #IT-03) and Orexin-B-SAP (Cat. #IT-20). Rats received 3-μg injections of Anti-DBH-SAP into the LC, or bilateral 57-80 ng injections of Orexin-SAP into the TMN. Both conjugates attenuated the increased REM sleep seen upon administration of almorexant without altering almorexant-induced changes in NREM sleep.