Browsing by Author "Little, Joel T."
Now showing 1 - 3 of 3
- Results Per Page
- Sort Options
Item ANGIOTENSIN II RECEPTOR TYPE-1A KNOCKDOWN IN SUBFORNICAL ORGAN PREVENTS SUSTAINED INCREASE IN MEAN ARTERIAL PRESSURE ASSOCIATED WITH CHRONIC INTERMITTENT HYPOXIA(2014-03) Saxena, Ashwini; Little, Joel T.; Nedungadi, Thekkethil P.; Cunningham, J. ThomasPurpose (a): Sleep apnea (SA) is associated with a sustained increase in mean arterial pressure (MAP) even during waking hours. Chronic intermittent hypoxia (CIH) models the hypoxemia associated with SA and produces elevated MAP during CIH and normoxia. Angiotensin II (Ang II) is implicated in the CIH associated increase in MAP. Subfornical organ (SFO), a forebrain circumventricular organ, lacks blood brain barrier and is a major site for the central effects of circulating Ang II. We investigated the effects of Ang II type 1a receptor knockdown (AT1aRKD) in the SFO on CIH hypertension in adult male rats. Methods (b): Adeno-associated viral vectors carrying GFP and either AT1aR shRNA or scrambled shRNA (SCM) were injected in SFO. Continuous measurements of mean arterial pressure, heart rate, respiratory rate, and activity were measured using radio-telemetry device implanted in abdominal aorta. Rats were exposed to cyclic hypoxia (3 min 21% O2 - 3 min 10% O2) for 8 hours/day for 7 days. Rats were sacrificed on Day 8. Results (c): Using laser-capture microdissection and qRT-PCR of amino-allyl RNA, AT1aRKD rats showed decreased SFO AT1aRmRNA in comparison with SCM rats. During intermittently-hypoxic light phase, the AT1aRKD rats exposed to CIH (3 min 10% O2 and 3 min room air cycles for 8 h during light phase for 7 d) exhibited significant increases in MAP vs. AT1aRKD-Normoxia group (p(p<0.05). During the normoxic dark phase, there was no difference in MAP between CIH and normoxic AT1aRKD rats (p=0.69). SCM-CIH group showed significant increase in MAP from SCM-Normoxia group during light phase CIH (p<0.001) and the normoxic dark phase (p<0.001). Conclusions (d): Our data indicate that AT1aRs in SFO may play a role in the sustained increases in MAP during normoxia associated with CIH.Item Effects of bile duct ligation on the inhibitory control of supraoptic vasopressin neurons(John Wiley & Sons, Inc., 2023-06-20) Aikins, Ato O.; Farmer, George E.; Little, Joel T.; Cunningham, J. ThomasDilutional hyponatremia due to increased plasma arginine vasopressin (AVP) is associated with liver cirrhosis. However, plasma AVP remains elevated despite progressive hypoosmolality. This study investigated changes to inhibitory control of supraoptic nucleus (SON) AVP neurons during liver cirrhosis. Experiments were conducted with adult male Sprague-Dawley rats. Bile duct ligation was used as a model of chronic liver cirrhosis. An adeno-associated virus containing a construct with an AVP promoter and either green fluorescent protein (GFP) or a ratiometric chloride indicator, ClopHensorN, was bilaterally injected into the SON of rats. After 2 weeks, rats received either BDL or sham surgery, and liver cirrhosis was allowed to develop for 4 weeks. In vitro, loose patch recordings of action potentials were obtained from GFP-labeled and unlabeled SON neurons in response to a brief focal application of the GABA(A) agonist muscimol (100 muM). Changes to intracellular chloride ([Cl]i) following muscimol application were determined by changes to the fluorescence ratio of ClopHensorN. The contribution of cation chloride cotransporters NKCC1 and KCC2 to changes in intracellular chloride was investigated using their respective antagonists, bumetanide (BU, 10 muM) and VU0240551 (10 muM). Plasma osmolality and hematocrit were measured as a marker of dilutional hyponatremia. The results showed reduced or absent GABA(A) -mediated inhibition in a greater proportion of AVP neurons from BDL rats as compared to sham rats (100% inhibition in sham vs. 47% in BDL, p = .001). Muscimol application was associated with increased [Cl]i in most cells from BDL as compared to cells from sham rats (chi(2) = 30.24, p < .001). NKCC1 contributed to the impaired inhibition observed in BDL rats (p < .001 BDL - BU vs. BDL + BU). The results show that impaired inhibition of SON AVP neurons and increased intracellular chloride contribute to the sustained dilutional hyponatremia in liver cirrhosis.Item Establishing Equivalent Aerobic Exercise Parameters Between Early-Stage Parkinson's Disease and Pink1 Knockout Rats(IOS Press, 2022-06-28) Salvatore, Michael F.; Soto, Isabel; Kasanga, Ella A.; James, Rachael; Shifflet, Marla K.; Doshier, Kirby; Little, Joel T.; John, Joshia; Alphonso, Helene M.; Cunningham, J. Thomas; Nejtek, Vicki A.BACKGROUND: Rodent Parkinson's disease (PD) models are valuable to interrogate neurobiological mechanisms of exercise that mitigate motor impairment. Translating these mechanisms to human PD must account for physical capabilities of the patient. OBJECTIVE: To establish cardiovascular parameters as a common metric for cross-species translation of aerobic exercise impact. METHOD: We evaluated aerobic exercise impact on heart rate (HR) in 21 early-stage PD subjects (Hoehn Yahr /=3 months, >/=3x/week. In 4-month-old Pink1 knockout (KO) rats exercising in a progressively-increased treadmill speed regimen, we determined a specific treadmill speed that increased HR to an extent similar in human subjects. RESULTS: After completing aerobic exercise for approximately 30 min, PD subjects had increased HR approximately 35% above baseline ( approximately 63% maximum HR). Motor and cognitive test results indicated the exercising subjects completed the timed up and go (TUG) and trail-making test (TMT-A) in significantly less time versus exercise-naive PD subjects. In KO and age-matched wild-type (WT) rats, treadmill speeds of 8-10 m/min increased HR up to 25% above baseline ( approximately 67% maximum HR), with no further increases up to 16 m/min. Exercised KO, but not WT, rats showed increased locomotor activity compared to an age-matched exercise-naive cohort at 5 months old. CONCLUSION: These proof-of-concept results indicate HR is a cross-species translation parameter to evaluate aerobic exercise impact on specific motor or cognitive functions in human subjects and rat PD models. Moreover, a moderate intensity exercise regimen is within the physical abilities of early-stage PD patients and is therefore applicable for interrogating neurobiological mechanisms in rat PD models.