Changes in Aperiodic (1/f Slope) Activity During a Picture-Word Interference Task: Effects of Congruency and Sequence Manipulations.

The renin‐angiotensin system (RAS) plays a pivotal role in the regulation of body fluid homeostasis by coordinating cardiovascular, renal, and behavioral responses to fluid imbalance. Activation of the RAS occurs primarily during extracellular fluid volume depletion, such as hypotension and/or hypovolemia, which stimulates renin release and production of angiotensin II (AngII) (Fitzsimons, ; Leenen & Stricker, ; Stricker et al., ). AngII acts peripherally to promote vasoconstriction and sodium retention but also centrally to increase sympathetic nerve activity, alter neuroendocrine function, and stimulate fluid intake. In regard to the latter, thirst responses to extracellular fluid volume depletion depend on AngII as nephrectomy or inhibition of angiotensin‐converting enzyme (ACE) markedly attenuates the ingestion of water induced by hypotension and hypovolemia (Evered & Robinson, ; Houpt & Epstein, ; Johnson et al., ; Katovich et al., ; Stocker et al., ). The central actions of AngII are largely mediated by angiotensin II type 1 receptors (Agtr1) (Fitzsimons, ). Intracerebroventricular administration of Agtr1 antagonists, such as losartan, markedly reduces pressor and dipsogenic responses to central AngII administration in rats (Kirby et al., ; Simpson et al., ; Widdop et al., ). In addition, thirst responses to central AngII are attenuated in Agtr1a (Li et al., ) or Agtr1b (Davisson et al., ) mice. Consistent with these observations, intracerebroventricular administration of Agtr1 antagonists attenuates water intake stimulated by hypotension or hypovolemia but not to acute hypernatremia (Buggy & Jonklaas, ; Fregly & Rowland, ; Simpson et al., ). Parallel studies using knockout models are limited. Agtr1a mice display reduced water intake in response to hypovolemia but not to water deprivation (Matsuda et al., ). Such experiments in Agtr1a mice are potentially confounded by two factors. First, systemic AngII does not reliably stimulate thirst in mice (Kobayashi et al., ; Rowland et al., ; Rowland & Fregly, ). Second, Agtr1a mice are profoundly hypotensive with baseline ABP approximately 20 mmHg lower than wild‐type controls (Chen et al., ; Ito et al., ; Sugaya et al., ). This is a potentially major confounding variable since the level of ABP influences thirst responses to several dipsogenic stimuli (Evered, ; Robinson & Evered, ; Stocker et al., ; Stocker et al., ). To overcome these limitations, we generated a novel Agtr1a rat using CRISPR/Cas9 and 11‐bp frameshift deletion in exon 3. Importantly, baseline ABP was approximately 10 mmHg lower in the Agtr1a versus wild‐type rats but no differences in heart rate. The Agtr1a was targeted as this is the predominant isoform expressed in circumventricular organs and the paraventricular nucleus of the hypothalamus–key regions involved in fluid balance and cardiovascular control (Lenkei et al., ; Lenkei et al., ). Using this novel Agtr1a rat, we assessed fluid intake and arterial blood pressure (ABP) in response to systemic AngII, hypotension, acute hypernatremia, and water deprivation.