scholarly journals Genetic targeting of adult Renshaw cells using a Calbindin 1 destabilized Cre allele for intersection with Parvalbumin or Engrailed1

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Alicia R. Lane ◽  
Indeara C. Cogdell ◽  
Thomas M. Jessell ◽  
Jay B. Bikoff ◽  
Francisco J. Alvarez
Keyword(s):  
Experimental Models ◽  
Renshaw Cells ◽  
Optimal Conditions ◽  
Spinal Neurons ◽  
Temporal Regulation ◽  
Spinal Interneurons ◽  
Spontaneous Recombination ◽  
Dorsal Horn Neurons ◽  
Genetic Targeting ◽  
The Brain

AbstractRenshaw cells (RCs) are one of the most studied spinal interneurons; however, their roles in motor control remain enigmatic in part due to the lack of experimental models to interfere with RC function, specifically in adults. To overcome this limitation, we leveraged the distinct temporal regulation of Calbindin (Calb1) expression in RCs to create genetic models for timed RC manipulation. We used a Calb1 allele expressing a destabilized Cre (dgCre) theoretically active only upon trimethoprim (TMP) administration. TMP timing and dose influenced RC targeting efficiency, which was highest within the first three postnatal weeks, but specificity was low with many other spinal neurons also targeted. In addition, dgCre showed TMP-independent activity resulting in spontaneous recombination events that accumulated with age. Combining Calb1-dgCre with Parvalbumin (Pvalb) or Engrailed1 (En1) Flpo alleles in dual conditional systems increased cellular and timing specificity. Under optimal conditions, Calb1-dgCre/Pvalb-Flpo mice targeted 90% of RCs and few dorsal horn neurons; Calb1-dgCre/En1-Flpo mice showed higher specificity, but only a maximum of 70% of RCs targeted. Both models targeted neurons throughout the brain. Restricted spinal expression was obtained by injecting intraspinally AAVs carrying dual conditional genes. These results describe the first models to genetically target RCs bypassing development.

Experimental Rodent Models of Vascular Dementia: A Systematic Review

2021 ◽  
Vol 19 ◽  
Author(s):  
Nidhi Tiwari ◽  
Jyoti Upadhyay ◽  
Mohd Nazam Ansari ◽  
Syed Shadab Raza ◽  
Wasim Ahmad ◽  
...  
Keyword(s):  
Vascular Dementia ◽  
Small Vessel Disease ◽  
Current Knowledge ◽  
Vascular Cognitive Impairment ◽  
Experimental Models ◽  
New Drugs ◽  
Amyloid Angiopathy ◽  
Vessel Disease ◽  
The Brain ◽  
Large Vessel Disease

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

scholarly journals Sotalol does not interfere with the antielectroshock action of selected second-generation antiepileptic drugs in mice

2021 ◽  
Author(s):  
Kinga K. Borowicz-Reutt ◽  
Monika Banach ◽  
Monika Rudkowska ◽  
Anna Stachniuk
Keyword(s):  
Antiepileptic Drugs ◽  
Second Generation ◽  
Antidepressant Drug ◽  
Experimental Models ◽  
Long Term Memory ◽  
Avoidance Task ◽  
Maximal Electroshock ◽  
Term Memory ◽  
The Brain

Abstract Background Due to blocking β-receptors, and potassium KCNH2 channels, sotalol may influence seizure phenomena. In the previous study, we have shown that sotalol potentiated the antielectroshock action of phenytoin and valproate in mice. Materials and methods As a continuation of previous experiments, we examined the effect of sotalol on the action of four chosen second-generation antiepileptic drugs (oxcarbazepine, lamotrigine, pregabalin, and topiramate) against the maximal electroshock in mice. Undesired effects were evaluated in the chimney test (motor impairment) and step-through passive-avoidance task (long-term memory deficits). Finally, brain concentrations of antiepileptics were determined by fluorescence polarization immunoassay, while those of sotalol by liquid chromatography–mass spectrometry. Results Sotalol at doses of up to 100 mg/kg did not affect the electroconvulsive threshold. Applied at doses of 80–100 mg/kg, sotalol did not affect the antielectroshock action of oxcarbazepine, lamotrigine, pregabalin, or topiramate. Sotalol alone and in combinations with antiepileptics impaired neither motor performance nor long-term memory. Finally, sotalol significantly decreased the brain concentrations of lamotrigine and increased those of oxcarbazepine and topiramate. Pharmacokinetic interactions, however, did not influence the final antielectroshock effects of above-mentioned drug combinations. On the other hand, the brain concentrations of sotalol were not changed by second-generation antiepileptics used in this study. Conclusion Sotalol did not reduce the antielectroshock action of four second-generation antiepileptic drugs examined in this study. Therefore, this antidepressant drug should not interfere with antiseizure effects of lamotrigine, oxcarbazepine, pregabalin, and topiramate in patients with epilepsy. To draw final conclusions, our preclinical data should still be confirmed in other experimental models and clinical conditions.

A critical role for central vasopressin in regulation of fever during bacterial infection

1992 ◽  
Vol 263 (6) ◽  
pp. R1235-R1240
Author(s):  
R. A. Cridland ◽  
N. W. Kasting
Keyword(s):  
Body Temperature ◽  
Arginine Vasopressin ◽  
Continuous Measurement ◽  
Critical Role ◽  
Experimental Models ◽  
Bacterial Endotoxins ◽  
Chronic Infusion ◽  
Live Bacteria ◽  
The Brain

Previous investigations on the antipyretic properties of arginine vasopressin have used bacterial endotoxins or pyrogens to induce fever. Because these experimental models of fever fail to mimic all aspects of the responses to infection, we felt it was important to examine the role of endogenously released vasopressin as a neuromodulator in febrile thermoregulation during infection. Therefore the present study examines the effects of chronic infusion of a V1-receptor antagonist or saline (via osmotic minipumps into the ventral septal area of the brain) on a fever induced by injection of live bacteria. Telemetry was used for continuous measurement of body temperature in the awake unhandled rat. Animals infused with the V1-antagonist exhibited fevers that were greater in duration compared with those of saline-infused animals. These results support the hypothesis that vasopressin functions as an antipyretic agent or fever-reducing agent in brain. Importantly, they suggest that endogenously released vasopressin may play a role as a neuromodulator in natural fever.

scholarly journals ANTI-PSYCHOTIC ACTIVITY OF PYRUS COMMUNIS JUICE

2017 ◽  
Vol 9 (4) ◽  
pp. 113
Author(s):  
Arzoo Singh Pannu ◽  
Milind Parle
Keyword(s):  
Experimental Models ◽  
Pyrus Communis ◽  
Anti Psychotic ◽  
Head Bobbing ◽  
Stereotypic Behaviour ◽  
Biochemical Estimation ◽  
Pear Juice ◽  
The Brain ◽  
Grooming Behaviour

Objective: The present study aim to investigate the anti-psychotic potential of pyrus communis in the rodents.Methods: The fresh juice of pyrus communis (Pear) was administered orally to rodents for 21 d and the anti-psychotic activity was assessed by in vitro methods viz ketamine induced stereotypic behaviour, pole climbing avoidance in rats and swim induced grooming behaviour experimental models. The biochemical estimation was done on 21 d.Results: The different concentrations of fresh pyrus communis juice was assayed. When pyrus communis juice (PCJ) was administered chronically for 21 d remarkably decreased ketamine induced falling, head-bobbing, weaving and turning counts. Administration of Pear juice significantly delayed the latency time taken by the animals to climb the pole in Cook’s pole climb apparatus. In swim induced grooming behaviour model, Pear juice significantly reduced swim induced grooming behaviour. Moreover, Pear juice significantly decreased the brain dopamine levels and inhibited acetyl cholinesterase activity. In the present study, Pear juice significantly enhanced reduced glutathione levels in the brains of mice, thereby reflecting enhanced scavenging of free radicals and in turn preventing occurrence of psychotic attack.Conclusion: The present study revealed that pyrus communis juice possessed significant anti-psychotic activity.

scholarly journals Animal models of brain metastasis

2021 ◽  
Vol 3 (Supplement_5) ◽  
pp. v144-v156
Author(s):  
Lauritz Miarka ◽  
Manuel Valiente
Keyword(s):  
Animal Models ◽  
Brain Metastasis ◽  
Metastatic Disease ◽  
Clinical Management ◽  
Experimental Models ◽  
Step Process ◽  
Critical Resource ◽  
The Brain

Abstract Modeling of metastatic disease in animal models is a critical resource to study the complexity of this multi-step process in a relevant system. Available models of metastatic disease to the brain are still far from ideal but they allow to address specific aspects of the biology or mimic clinically relevant scenarios. We not only review experimental models and their potential improvements but also discuss specific answers that could be obtained from them on unsolved aspects of clinical management.

Abstract MP57: Chronic Inhibition Of Brain Rhomboid-like Protein 2 (irhom2) Activity Decreases Arterial Blood Pressure In Salt-sensitive Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Mazher Mohammed ◽  
Mona Elgazzaz ◽  
Clara Berdasco ◽  
Eric D Lazartigues
Keyword(s):  
Blood Pressure ◽  
Neutralizing Antibody ◽  
Experimental Models ◽  
Arterial Blood ◽  
Artificial Cerebrospinal Fluid ◽  
Tnf Α ◽  
Significant Attenuation ◽  
Factor Α ◽  
Salt Sensitive Hypertension ◽  
The Brain

We previously reported that ADAM17 (aka tumor necrosis factor-α convertase) is critical for the development of hypertension in experimental models and patients. Recent studies highlighted that ADAM17’s formation of TNF-α relies on prior maturation of this sheddase, controlled by the rhomboid-like protein 2 (iRhom2) specifically in microglia. Genetic deletion of iRhom2 in mice shows significant attenuation of TNF-α and ADAM17 activity in a tissue specific manner. Here, we hypothesized that silencing iRhom2 activity specifically in the brain would decrease blood pressure (BP) in the DOCA-salt model of hypertension, in mice. Uninephrectomized mice were implanted subcutaneously (sc) with DOCA-pellets (50 mg) and provided with 1% saline in drinking water. In addition, mice were chronically implanted with an icv cannula connected to a sc osmotic minipump for delivery of: (1) iRhom2-siRNA (9.6 μg/kg/day), (2) scrambled siRNA (SCR 0.2 μg/kg/day), (3) ADAM17 antibody (ADAM17-Ab; 23.8 μg/kg/day) or (4) artificial cerebrospinal fluid (aCSF) for 2 weeks while BP was recorded by telemetry. DOCA-salt treatment led to a significant increase in BP in the control groups (SCR: 156 ±3 mmHg and aCSF: 161 ±1 mmHg; n=3/group; p<0.001) compared to baseline values (122 ±2 mmHg; n=12). ICV infusion of iRhom2-siRNA or ADAM17 neutralizing antibody for 2-weeks in DOCA-salt-treated mice resulted in a significant attenuation of BP (iRhom2-siRNA: 152 ±2 mmHg and ADAM17-Ab: 151 ±2 mmHg n=3/group, p<0.001). These data suggest that: 1) Selective silencing of iRhom2 from microglia is as potent as ADAM17 neutralization throughout the brain in lowering BP and 2) iRhom2 is a potential new therapeutic target for the treatment of salt-sensitive hypertension.

Role of spinal neurons in the maintenance of elevated sympathetic activity: a novel therapeutic target?

2020 ◽  
Vol 319 (3) ◽  
pp. R282-R287
Author(s):  
Maycon I. O. Milanez ◽  
Erika E. Nishi ◽  
Cássia T. Bergamaschi ◽  
Ruy R. Campos
Keyword(s):  
Cardiovascular Diseases ◽  
Therapeutic Target ◽  
Sympathetic Activity ◽  
Spinal Neurons ◽  
Potential Therapeutic Target ◽  
Present Evidence ◽  
Extensive Range ◽  
Vasomotor Activity ◽  
The Brain

The control of sympathetic vasomotor activity involves a complex network within the brain and spinal circuits. An extensive range of studies has indicated that sympathoexcitation is a common feature in several cardiovascular diseases and that strategies to reduce sympathetic vasomotor overactivity in such conditions can be beneficial. In the present mini-review, we present evidence supporting the spinal cord as a potential therapeutic target to mitigate sympathetic vasomotor overactivity in cardiovascular diseases, focusing mainly on the actions of spinal angiotensin II on the control of sympathetic preganglionic neuronal activity.

Tonic descending modulation of spinal neuronal responses to activation of renal receptors

1993 ◽  
Vol 265 (6) ◽  
pp. R1291-R1303
Author(s):  
A. Standish ◽  
M. A. Vizzard ◽  
W. S. Ammons
Keyword(s):  
Renal Artery ◽  
Renal Vein ◽  
Cell Activity ◽  
Neuronal Responses ◽  
Spinal Neurons ◽  
Descending Modulation ◽  
Spinal Circuitry ◽  
Renal Receptor ◽  
Somatic Input ◽  
The Brain

Experiments were conducted in anesthetized cats to determine if spinal neuronal responses to activation of renal receptors are tonically modulated by descending spinal pathways. Eighty-seven thoracolumbar spinal neurons with renal and somatic input were tested for responses to occlusion of the renal vein, renal artery, and ureter before, during, and after cooling the spinal cord rostral to the recording site. Cooling increased the number of neurons that responded as well as the magnitude of the responses to renal vein (RVO), renal artery (RAO), and ureteral occlusion (UO). RVO increased cell activity of 21 neurons from 12.5 +/- 2.7 to 31.7 +/- 6.0 spikes/s during cooling. UO increased cell activity of 24 neurons from 9.0 +/- 2.1 before cooling to 25.0 +/- 4.9 spikes/s during cooling. Cold block increased the magnitude of both types of responses to RAO that were due to mechanical deformation of the renal artery and prolonged renal ischemia. These data show that the majority of spinal neuronal responses to renal receptor stimulation are modulated by tonic inhibitory influences. Thus these results provide a mechanism by which the brain may control spinal circuitry that underlies reflexes of renal origin.

scholarly journals Acute Astrocyte Activation in Brain Detected by Mri: New Insights into T1 Hypointensity

2007 ◽  
Vol 28 (3) ◽  
pp. 621-632 ◽  
Author(s):  
Nicola R Sibson ◽  
John P Lowe ◽  
Andrew M Blamire ◽  
Matthew J Martin ◽  
Tiho P Obrenovitch ◽  
...  
Keyword(s):  
Experimental Models ◽  
Low Flow ◽  
Astrocyte Activation ◽  
Tissue Water ◽  
Signal Change ◽  
Apparent Diffusion ◽  
Acute Increase ◽  
Magnetic Resonance Imaging Mri ◽  
The Brain ◽  
Intrastriatal Injection

Increases in the T1 of brain tissue, which give rise to dark or hypointense areas on T1-weighted images using magnetic resonance imaging (MRI), are common to a number of neuropathologies including multiple sclerosis (MS) and ischaemia. However, the biologic significance of T1 increases remains unclear. Using a multiparametric MRI approach and well-defined experimental models, we have experimentally induced increases in tissue T1 to determine the underlying cellular basis of such changes. We have shown that a rapid acute increase in T1 relaxation in the brain occurs in experimental models of both low-flow ischaemia induced by intrastriatal injection of endothelin-1 (ET-1), and excitotoxicity induced by intrastriatal injection of N-methyl-d-aspartate (NMDA). However, there appears to be no consistent correlation between increases in T1 relaxation and changes in other MRI parameters (apparent diffusion coefficient, T2 relaxation, or magnetisation transfer ratio of tissue water). Immunohistochemically, one common morphologic feature shared by the ET-1 and NMDA models is acute astrocyte activation, which was detectable within 2 h of intracerebral ET-1 injection. Pretreatment with an inhibitor of astrocyte activation, arundic acid, significantly reduced the spatial extent of the T1 signal change induced by intrastriatal ET-1 injection. These findings suggest that an increase in T1 relaxation may identify the acute development of reactive astrocytes within a central nervous system lesion. Early changes in T1 may, therefore, provide insight into acute and reversible injury processes in neurologic patients, such as those observed before contrast enhancement in MS.

Spinomuscular Coherence in Monkeys Performing a Precision Grip Task

2008 ◽  
Vol 99 (4) ◽  
pp. 2012-2020 ◽  
Author(s):  
Tomohiko Takei ◽  
Kazuhiko Seki
Keyword(s):  
Spinal Cord ◽  
Sensorimotor Integration ◽  
Unique Feature ◽  
Cervical Spinal Cord ◽  
Precision Grip ◽  
Muscle Physiology ◽  
Field Potentials ◽  
Spinal Interneurons ◽  
Arm Muscles ◽  
The Brain

We recorded local field potentials (LFPs) from cervical spinal cord (C5–C8) in monkeys performing a precision grip task and examined their coherence with electromyographic (EMG) activities (spinomuscular coherence) recorded from hand and arm muscles. Among 164 LFP-EMG pairs, significant coherence was found in 34 pairs (21%). We classified the coherence into two groups based on its frequency range, narrowband coherence, and broadband coherence. The narrowband coherence was restricted to discrete frequencies in the range of 14–55 Hz and was widespread throughout the superficial and deep gray matter. In contrast, the broadband coherence distributed between 10 and 95 Hz and was found only in the ventral half of the spinal cord. The narrowband coherence suggests that oscillations, which have been described in many motor control areas of the brain, could also pass though spinal interneurons to affect motor output and sensorimotor integration. On the other hand, the broadband coherence could be a unique feature of spinal motoneuron-muscle physiology.

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