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. Author manuscript; available in PMC: 2025 Sep 2.
Published in final edited form as: Auton Neurosci. 2025 Jun 18;260:103315. doi: 10.1016/j.autneu.2025.103315

Blunted pressor response to peripheral sensory afferent nerve stimulation in intracerebroventricular-streptozotocin injected rats☆

Ayumi Fukazawa a,b,1, Norio Hotta c,1, Hoda Yeganehjoo d, Amane Hori a,b, Han-Kyul Kim a,e, Gary A Iwamoto f, Scott A Smith a, Wanpen Vongpatanasin e, Masaki Mizuno a,*
PMCID: PMC12400199  NIHMSID: NIHMS2105861  PMID: 40561701

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder. It is characterized by synaptic loss and the increase of amyloid β (Aβ) in the brain often detrimentally affecting function. Brainstem is the key central integration site for sensory input from working skeletal muscle. Stimulation of skeletal muscle afferent fibers during muscle contraction increases blood pressure. However, whether AD alters or preserves the central processing of peripheral sensory afferent signals remains to be elucidated. Thus, we tested the hypothesis that the magnitude of the pressor response is functionally altered in intracerebroventricular-streptozotocin injected rats (ICV-STZ). Streptozotocin (3 mg/kg) was intracerebroventricularly injected into the lateral ventricle of male Sprague–Dawley rats. In parallel, a separate group of rats were treated with ICV saline as a vehicle control. Spatial learning and memory function were assessed using the Morris Water Maze behavioral test. Results demonstrate that ICV-STZ rats had a significantly longer time to reach a target platform compared to controls (P = 0.0046). ICV-STZ injection also significantly increased brainstem Aβ1–40 (P = 0.0082), but not Aβ1–42 (P = 0.0744). Further, the peak pressor and cardioaccelerator responses to tibial nerve stimulation were significantly attenuated in ICV-STZ rats compared to controls (ΔMAP: P = 0.0003, ΔHR: P = 0.0035). The findings suggest that the cardiovascular responses to electrical stimulation of sensory afferents are blunted in ICV-STZ rats.

Keywords: Streptozotocin, Sporadic Alzheimer’s disease, Amyloid β, Mechanoreflex, And metaboreflex

1. Introduction

As the population ages, the number of people with neurodegenerative diseases, such as Alzheimer’s disease (AD), is increasing. More than fifty-five million people are estimated to live with dementia worldwide, with this number projected to rise to 153 million by 2050 (GBD 2019 Dementia Forecasting Collaborators, 2022). To our best knowledge, the impact of AD on blood pressure regulation is highly controversial. For instance, it has been reported that high blood pressure or elevated blood pressure variability is associated with cognitive decline and onset of AD (de Heus et al., 2019; Lee et al., 2022; Sible and Nation, 2025). On the other hand, there are studies showing that low blood pressure is associated with an increased risk of dementia (Guo et al., 1997; Launer et al., 1995; Morris et al., 2001). Moreover, blood pressure levels have been shown to decrease with advancing clinical symptoms of AD (Skoog et al., 1996). Furthermore, no significant relation was observed between AD risk and high blood pressure (Lindsay et al., 2002). The quantitative meta-analysis showed that there was no significant difference in incidence of AD between subjects with and without hypertension (Guan et al., 2011). Thus, the association between blood pressure and AD has been inconclusive.

AD is the most common type of dementia (Lee et al., 2024) and Amyloid β (Aβ) plaques in the brain are the main pathological hallmarks (Hampel et al., 2021). Earlier studies suggest that AD is a chronic neurodegenerative disease leading to cognitive declines mediated by synaptic loss (DeKosky and Scheff, 1990; Mecca et al., 2022; Terry et al., 1991). Data collected over the past few decades implicate the soluble forms of Aβ in brain toxicity (Kopeikina et al., 2012; Spires-Jones and Hyman, 2014). For example, evidence indicates that the soluble form of Aβ is directly toxic to synapses (Hong et al., 2018; Shankar et al., 2008). Thus, it is likely that the progression of AD and increase of Aβ may affect signal transduction processes in the brain.

Stimulation of skeletal muscle afferent fibers during muscle contraction increases blood pressure, a response elicited by the exercise pressor reflex (EPR) (McCloskey and Mitchell, 1972). In this reflex, somatosensory signals from contracting skeletal muscle which participate in raising blood pressure and heart rate are transmitted via thinly myelinated group III and unmyelinated group IV afferent fibers. Most group III afferents are activated at the onset of muscle contraction with associated receptors responding primarily to mechanical distortion (i.e., the muscle mechanoreflex), whereas the majority of group IV fibers subserve chemically sensitive receptors activated by the by-products of skeletal muscle metabolism (i.e., the muscle metaboreflex) (Kaufman et al., 1983). The first site of synapse for most muscle group III and IV afferents is the dorsal horn of the spinal cord. Second-order neurons receiving input from skeletal muscle afferents project from the dorsal horn to the cardiovascular control centers located in the hindbrain (Iwamoto et al., 1984; Iwamoto et al., 1982). Then, the rostral ventrolateral medulla (RVLM) directly receives input from the spinal cord and putatively through a relay in the nucleus tractus solitarius (NTS) through a projection described as moderate (Craig, 1995; Potts et al., 2002). It is well known that the RVLM within the brainstem plays a crucial role in the control of the cardiovascular system during exercise (Nolán and Waldrop, 1997). However, to date, it has not been elucidated whether AD alters the signal transduction associated with the EPR or the extent to which AD affects cardiovascular responses to activation of muscle afferents. Blood pressure variability or blood pressure levels, which are associated with AD (de Heus et al., 2019; Lee et al., 2022; Sible and Nation, 2025), are largely elevated during the day-time compared to night-time due to physical activity. Since skeletal muscle afferents play a crucial role in cardiovascular regulation during physical activity, it is clinically and physiologically relevant to clarify the impact of AD on circulatory regulation via skeletal muscle afferents.

Streptozotocin (STZ) is a naturally occurring chemical compound produced by Streptomyces achromogenes (Ghasemi and Jeddi, 2023). It has been reported that intracerebroventricular (ICV) injection of STZ leads to sporadic AD, which is the most common form of AD [approximately 95 % of people with AD (Kloppenborg et al., 2008; Lista et al., 2015)]. Increasing evidence suggests that ICV injection of STZ elicits sporadic AD-like pathophysiology including alterations in: the processing of amyloid precursor protein (Alluri et al., 2020), glucose metabolism (Deng et al., 2009), insulin signaling (Deng et al., 2009), synaptic function (Kadhim et al., 2022; Rai et al., 2014) and apoptosis (Rajkumar et al., 2022). As such, it is reasonable to suggest that an AD rat model generated via ICV injection of STZ represents the most prevalent type of AD. The purpose of this study was therefore to investigate the cardiovascular responses to stimulation of muscle afferents in intracerebroventricular-streptozotocin injected rats (ICV-STZ rat). We hypothesized that ICV-STZ rats mediate an “altered” or “preserved” pressor response to activation of peripheral sensory afferents since it is not certain whether it will increase, decrease, or preserve due to conflicting clinical outcomes. In this investigation, we examined whether ICV-STZ rats demonstrated “altered” or “preserved” pressor responses to mechano- or metabo-reflex stimulation of hindlimb skeletal muscle. In addition, to assess central signal integration of mechano- and metabo-sensitive afferent fibers, we further investigated whether the pressor response to tibial nerve stimulation (a maneuver that stimulates both set of afferents simultaneously) was “altered” or “preserved” in AD rats. As mentioned, the impact of AD on blood pressure regulation remains highly controversial. Although individuals with early-stage AD exhibited cardiovascular responses similar to those of nondemented controls (Billinger et al., 2011), it is technically challenging to exclude various factors (e.g., arterial stiffness or sarcopenia) affecting blood pressure responses during exercise, especially in older adults. To our knowledge, no studies have investigated the effect of experimentally induced AD on cardiovascular responses to simulated exercise. Our findings may contribute to elucidating the reasons behind the inconsistencies reported in earlier studies.

2. Methods

2.1. Ethical approval

This study was performed in accordance with the US Department of Health and Human Services NIH Guide for the Care and Use of Laboratory Animals. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the University of Texas Southwestern Medical Center (no. 2019-102849).

2.2. Animals

Sixty-six healthy male Sprague-Dawley (SD) rats were used for physiological and biochemical studies. The animal room was maintained at 22–24 °C with 40–60 humidity with 12 h light and dark cycle. All rats were given ad libitum access to food and water for the duration of this study.

2.3. Streptozotocin injection

SD rats were given a single ICV injection of 3 mg/kg STZ, as described previously (Chen et al., 2013; Grieb, 2016). Isoflurane anesthetized animals were placed on a stereotaxic head unit (David Kopf Instruments, Tujunga, CA, USA) and a small hole was first drilled into the skull. Then, a 33-gauge needle (WPI, Sarasota, FL, USA) was implanted in the right lateral ventricle. The injection coordinates were 0.8 mm posterior, 1.5 mm lateral, and 3.6 mm ventral to the bregma and injection volume was 10 μL. In parallel, a separate group of rats were treated with ICV saline as a vehicle control.

2.4. Morris water maze

To assess spatial learning and memory, the Morris Water Maze (MWM) test was performed 10 weeks after ICV injection of experimental solutions at the UT Southwestern Medical Center Rodent Behavior Core (22 weeks old). The water maze consists of a round pool, 142cm in diameter and 33cm deep, filled with water (22 ± 1 °C). Black non-toxic tempera paint was used on the pool to enhance contrast so a camera could distinguish the rat from the pool. Several large black shapes were attached to the walls of the pool as visual cues (approximately 60–90 cm from the edge of the pool). The time to reach a submerged translucent target platform (escape latency) was recorded. Rats performed 4 MWM trials on each of 4 consecutive days.

2.5. Amyloid β measurement

Samples were collected 10 weeks after ICV injection of test solutions (19 weeks old). Cerebrospinal fluid (CSF) was collected under isoflurane anesthesia. Blood samples were taken via cardiac puncture under isoflurane anesthesia and centrifuged to collect plasma. The anesthetized rats were subsequently sacrificed and brain tissue (cortex, hippocampus, and entire brainstem) dissected and harvested. Samples were stored at −80 °C until analysis. Amyloid β1–40 and 1–42 were determined using Human/Rat β Amyloid(40) ELISA Kit Wako II and Human/Rat β Amyloid(42) ELISA Kit Wako, High Sensitive (FUJIFILM Wako Pure Chemical Corporation, Osaka, Japan), respectively. Intra-assay CV standards were 3.4 % (range: 0.6–8.1 %, R2 = 0.9985) for Aβ1–40 and 2.7 % (range: 1.0–6.3 %, R2 = 0.9987) for Aβ1–42.

2.6. Recording of blood pressure and heart rate in vivo

2.6.1. General surgery procedure for blood pressure recording

All experiments were performed 6–14 weeks after ICV injection of either STZ or vehicle (weeks of age: 19 ± 2 vs. 18 ± 5, respectively, P = 0.8314, weeks after treatment: 10 ± 2 vs. 10 ± 3 respectively, P = 0.8417). The general surgical procedure used in this study has been described previously (Estrada et al., 2024; Mizuno et al., 2016). Rats were anesthetized with 1–4 % of isoflurane in oxygen and intubated for mechanical ventilation. To stabilize fluid balance and maintain baseline arterial blood pressure (ABP), a continuous infusion of sodium bicarbonate solution (8 mL 1 M NaHCO3 and 40 ml 5 % dextrose in 152 mL lactated ringer’s injection solution) was continuously established via the jugular vein at the rate of 3–5 mL/h/kg. ABP was continuously measured by a pressure transducer connected to a left carotid arterial catheter (MLT0380/D, ADInstrument Inc., Colorado Springs, CO, USA). Needle electrodes were placed on the back of the animal to record electrocardiograph signals (ECGs). Heart rate (HR) was derived from the R wave of the ECG recording. All animals were held in stereotaxic head unit (David Kopf Instruments, Tujunga, CA, USA) and a precollicular decerebration was performed rendering the animal insentient. In this procedure, dexamethasone (0.2 mg) was given intravenously to minimize brain edema. The upper skull and dura were removed. Subsequently, the cerebrum neural tissue rostral to the superior colliculus were removed by suction aspiration. Cotton balls were used to pack the cranial cavity. Post-decerebration, isoflurane anesthesia was discontinued and a minimum recovery period of 1 h was employed before beginning any experimental procedure.

2.6.2. Experimental protocols for tibial nerve stimulation

The tibial nerve of the right hindlimb was surgically isolated by blunt dissection, and a pair of stainless-steel electrodes was used to stimulate the nerve, eliciting a pressor response [10 × motor threshold (MT) and 50 × MT, 0.75 ms, 20 Hz, for 30 s]. The intensity of 10 × MT has been shown to be sufficient for activation of group I-IV afferent fibers (Harms et al., 2016; McCallister et al., 1986). The MT was determined by progressively increasing the currents of single pulse applied to the tibial nerve until muscle twitch was observed. In this experiment, the rats were paralyzed with pancuronium bromide (0.2 mg i.v.) to prevent muscle contraction.

2.6.3. Experimental protocols for mechanical stimulation

Baseline resting tension in the hind-limb muscles was set to 70–100 g. The muscles were manually and passively stretched for 30 s to generate a mechanical stimulus, following the maximum tension curve obtained by electrical stimulation of the tibial nerve (0.1 ms, 40 Hz, 3 × MT, 30 s).

2.6.4. Experimental protocols for chemical stimulation

The circulation of the hindlimb was surgically isolated for the direct injection of chemical into the arterial supply of the right leg, as previously described (Hori et al., 2022). Briefly, the left common iliac artery was catheterized and the tip of catheter advanced to the bifurcation of the abdominal aorta. A reversible ligature placed around the right iliac vein was used to trap the injectate in the hindlimb. To selectively activate the chemically-sensitive afferent fibers associated with skeletal muscle metaboreflex, capsaicin (0.3 μg/100 μL, dissolved in 50 % ethanol and then diluted with 0.9 % saline) was administrated into the right common iliac artery of the hindlimb. Our previous studies have confirmed that the repeated administration of capsaicin induces reproducible pressor and sympathetic responses without the occurrence of desensitization (Ishizawa et al., 2021; Mizuno et al., 2015; Mizuno et al., 2011).

2.6.5. End-experiment procedure

Decerebrate animals were humanely euthanized by intravenous injection of saturated potassium chloride (4 M, 2 mL/kg iv). The heart, lungs and epididymal adipose tissue were excised and weighed. Additionally, tibial length was measured.

2.6.6. Data acquisition and analysis

Data was analyzed as previously described (Mizuno et al., 2016). Data for MAP, HR and muscle tension was obtained with LabChart 8 data acquisition software (ADInsturuents Inc) and PowerLab analog-to-digital converter (PowerLab8/30, ADInsturuents Inc) at a 1 kHz sampling rate. One-second averages of MAP, HR, and tension were used for each analysis. Baseline values were determined by evaluating 30 s of recorded data immediately before the stimulation. The maximal MAP, HR, and tension responses to stimulation were defined as the peak change from baseline (ΔMAP: mmHg, ΔHR: bpm, Δtension: g). The integrated changes in MAP, HR, and tension in response to stimulation are presented as area under curve over 30 s (∫ΔMAP: mmHg × s, ∫ΔHR: bpm × s, ∫Δtension: g × s)

2.7. Statistical analysis

The Shapiro-Wilk test was first performed to confirm data normality. In MWM tests, statistical analyses were performed using repeated two-way analysis of variance (ANOVA) to examine the effects of group (control vs. ICV-STZ) and day. If significant interactions or main effects of group or day were observed, the Tukey–Kramer multiple-comparison test was performed to examine the differences among groups. Physiological data obtained from tibial nerve stimulation maneuvers were analyzed by repeated two-way ANOVA and included main effects for group and stimulation intensity. Group comparisons (control vs. ICV-STZ) in passive stretch maneuvers, capsaicin injections and Aβ concentrations were made with either Student’s unpaired t-test or Mann–Whitney U tests as appropriate.

Analyses were conducted using statistical software (Prism 9.0, GraphPad Software, San Diego, CA, USA). Statistical significance was defined as P < 0.05. Data are presented as the mean ± SD.

3. Results

3.1. Morris water maze

The body weight before performing the MWM test in ICV-STZ was significantly lower than that in control group (449 ± 29 vs. 415 ± 35 g, P = 0.0291). Fig. 1 shows individual data obtained from the MWM test. Significant main effects of group (control vs. ICV-STZ, P = 0.0046) and day (P < 0.001) were observed. The escape latency on the first day was significantly longer than those on the other days (Day 1 vs. Day 2: P < 0.0001, Day 1 vs. Day 3: P < 0.0001, Day 1 vs. Day 4: P < 0.0001). No significant differences were found among the other days.

Fig. 1. Spatial memory and learning evaluated by Morris Water Maze test were impaired in ICV-STZ rats.

Fig. 1.

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ICV: intracerebroventricular, STZ: streptozotocin. Values are mean ± SD.

3.2. Aβ concentration

The body weight before collecting samples in ICV-STZ was significantly lower than that in control group (451 ± 18 vs. 405 ± 30 g, P = 0.001). Significant differences in plasma, CSF, cortex and hippocampus Aβ1–40 were not observed between control and ICV-STZ groups [plasma Aβ1–40: 188 ± 19 vs. 191 ± 24 pg/mL, P = 0.7627, CSF Aβ1–40: 1676 ± 310 vs. 1497 ± 353 pg/mL, P = 0.2978, cortex Aβ1–40: 127 ± 16 vs. 134 ± 15 pg/mL, P = 0.3762, hippocampus Aβ1–40: 127 ± 16 vs. 144 ± 34 pg/mL, P = 0.3282 (Fig. 2A)]. Entire brainstem Aβ1–40 was significantly higher in the ICV-STZ group than in the control group [121 ± 5 vs. 130 ± 7 pg/mL, P = 0.0082 (Fig. 2A)].

Fig. 2. Amyloid β1–40 (A) and 1–42 (B) concentrations in control and ICV-STZ rats.

Fig. 2.

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Aβ: amyloid β, ICV: intracerebroventricular, STZ: streptozotocin. Values are mean ± SD. * data point evaluated as an outlier by Grubbs’s test. Even when this data point was excluded from the analysis, the concentration of Aβ1–42 in the brainstem was not significantly different between groups (P = 0.1482). Note that even after excluding the data from the rat whose brainstem Aβ1–42 levels was an outlier, the significance of the variables remained unchanged (CSF Aβ1–42: control vs. ICV-STZ, 320 ± 70 vs. 257 ± 62 pg/mL, P = 0.0905; brainstem Aβ1–40: 121 ± 5 vs. 129 ± 7 pg/mL, P = 0.0175).

The plasma, cortex and hippocampus Aβ1–42 concentration in the ICV-STZ group were not significantly different from those in the control group [plasma Aβ1–42: 23 ± 3 vs. 24 ± 3 pg/mL, P = 0.8583, cortex Aβ1–42: 28 ± 4 vs. 29 ± 3 pg/mL, P = 0.4258, hippocampus Aβ1–42: 27 ± 3 vs. 27 ± 2 pg/mL, P = 0.6454 (Fig. 2B)]. The level of CSF Aβ1–42 in ICV-STZ group tended to be lower than that in control group [320 ± 70 vs. 258 ± 57 pg/mL, P = 0.0731 (Fig. 2B)]. Entire brainstem Aβ1–42 tended to be higher in ICV-STZ group than in control group [23 ± 2 vs. 24 ± 1 pg/mL, P = 0.0774 (Fig. 2B)].

3.3. Pressor response to chemical and mechanical stimulation

Table 1 summarizes morphometric characteristics and baseline hemodynamics before and after decerebration in each experimental procedure. Although the differences did not reach statistical significance, the ICV-STZ group tended to have lower body weight and epididymal adipose tissue weight compared with the control group (body weight: P = 0.0987, epididymal adipose tissue: P = 0.0714). There were no significant differences in heart weight to body weight ratio (P = 0.1489), heart weight to tibial length ratio (P = 0.6820), lung weight to body weight ratio (P = 0.9282), and fasting blood glucose concentrations (P = 0.2169) between control and ICV-STZ groups. Baseline MAP and HR under 1 % isoflurane as well as after decerebration were not significantly different between control and ICV-STZ groups [MAP (under 1 % isoflurane): P = 0.8857, HR (under 1 % isoflurane): P = 0.3259, MAP (after decerebration): P = 0.7300, HR (after decerebration): P = 0.9220]. Additionally, there was no significant difference in motor threshold between control and ICV-STZ groups (P = 0.9884).

Table 1.

Morphometric characteristics, fasting blood glucose and baseline hemodynamics.

Control ICV-STZ P value
N 14 17
Body weight, g 407 ± 44 385 ± 31 0.0987
Heart weight/body weight, mg/g 2.3 ± 0.4 2.4 ± 0.2 0.1489
Heart weight/tibial length, mg/mm 23 ± 4 24 ± 3 0.6820
Lung weight/body weight, mg/g 7.7 ± 1.4 7.7 ± 0.3 0.9282
Epididymal adipose tissue, g 5.6 ± 0.5 4.5 ± 1.4 0.0714
Fasting blood glucose, mg/dL 94 ± 14 86 ± 19 0.2169
(n = 15)
1 % Isoflurane anesthesia
 MAP, mmHg 113 ± 30 115 ± 32 0.8857
 HR, bpm 329 ± 35 317 ± 31 0.3259
After decerebration
 MAP, mmHg 104 ± 26 100 ± 31 0.7300
 HR, bpm 460 ± 53 462 ± 38 0.9220
Tibial nerve stimulation 17 ± 7 17 ± 7 0.9884
motor threshold, μA (n = 16)
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Values are means ± SD

3.3.1. Cardiovascular responses to tibial nerve stimulation

Representative ABP responses to tibial nerve stimulation performed at 10 × and 50 × motor threshold in control and ICV-STZ are show in Fig. 3A & B. Significant main effects of group and stimulation intensity were observed in the measured ΔMAP [group: P = 0.0003, stimulation intensity: P = 0.0111 (Fig. 3C)] and ∫ΔMAP [group: P = 0.0010, stimulation intensity: P = 0.0007 (Fig. 3E)]. A significant main effect of group on ΔHR was observed [P = 0.0035 (Fig. 3D)]. The integrated HR did not change in either group [interaction (group × stimulation intensity): P = 0.7183, group: P = 0.2220, stimulation intensity: P = 0.6724 (Fig. 3F)].

Fig. 3. Summary data showing cardiovascular responses to activation of tibial nerve in control and ICV-STZ rats.

Fig. 3.

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Representative pressor responses to tibial nerve stimulation performed at 10 × and 50 × motor threshold in control (A) and ICV-STZ (B). Peak mean arterial pressure (MAP) and heart rate (HR) in response to stimulation of tibial nerve activation (C and D). Integrated changes in MAP and HR are presented as an area under the curve (E and F). ICV: intracerebroventricular, STZ: streptozotocin. Value are means ± SD.

3.3.2. Cardiovascular responses to passive hindlimb stretch

Representative pressor responses and tension development to passive hindlimb stretch in control and ICV-STZ are demonstrated in Fig. 4A & B. No significant differences were observed in the peak changes in MAP, HR and tension during passive stretch between control and ICV-STZ groups [ΔMAP: 26 ± 19 vs. 21 ± 19 mmHg, P = 0.4536 (Fig. 4C), ΔHR: 4.2 ± 3.6 vs. 3.6 ± 3.2 bpm, P = 0.6424 (Fig. 4D), Δtension: 1.2 ± 0.4 vs. 1.1 ± 0.2 kg, P = 0.3023 (Fig. 4E)]. The integrated pressor response to passive stretch in ICV-STZ group tended to be lower than that in control group [245 ± 261 vs. 97 ± 133 mmHg × s, P = 0.0783 (Fig. 4F)]. The integrated HR and tension were not different between control and ICV-STZ groups [∫ΔHR: 25 ± 64 vs. 23 ± 78 bpm × s, P = 0.9447 (Fig. 4G), ∫Δtension: 21 ± 7 vs.19 ± 5 kg × s, P = 0.3546 (Fig. 4H)].

Fig. 4. Summary data showing cardiovascular responses to passive stretch in control and ICV-STZ rats.

Fig. 4.

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Representative peak pressor responses to hindlimb passive stretch and developed tension in control (A) and ICV-STZ (B). Peak mean arterial pressure (MAP), heart rate (HR) and developed tension in response to mechanoreflex activation (C, D and E). Integrated changes in MAP, HR, and tension are presented as an area under the curve (F, G and H). ICV: intracerebroventricular, STZ: streptozotocin. Values are mean ± SD.

3.3.3. Cardiovascular responses to intraarterial capsaicin injection

Representative blood pressure responses to intraarterial capsaicin injection in control and ICV-STZ are demonstrated in Fig. 5A & B. Both the peak changes in MAP and HR were not different between control and ICV-STZ groups [ΔMAP: 47 ± 17 vs. 37 ± 17 mmHg, P = 0.1122 (Fig. 5C), ΔHR: 6.5 ± 3.1 vs. 5.4 ± 4.2 bpm, P = 0. 4532 (Fig. 5D)]. Likewise, the integrated MAP and HR were not different between control and ICV-STZ groups [∫ΔMAP: 446 ± 167 vs. 443 ± 230 mmHg × s, P = 0.9793 (Fig. 5E), ∫ΔHR: 35 ± 51 vs. 25 ± 122 bpm × s, P = 0.7883 (Fig. 5F)].

Fig. 5. Summary data showing cardiovascular responses to capsaicin injection in control and ICV-STZ rats.

Fig. 5.

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Representative peak pressor responses to capsaicin injection in control (A) and ICV-STZ (B). Peak mean arterial pressure (MAP) and heart rate (HR) in response to metaboreflex activation (C and D). Integrated changes in MAP and HR are presented as an area under the curve (E and F). ICV: intracerebroventricular, STZ: streptozotocin. Values are mean ± SD.

4. Discussion

The major findings of the current investigation were that ICV-STZ rats showed an attenuated pressor response to tibial nerve stimulation, but not passive stretch of hindlimb muscle nor hindlimb intraarterial capsaicin injection.

4.1. Special memory, Aβ concentration, and baseline MAP in ICV-STZ rats

The ICV-STZ-induced sporadic AD rat model is commonly used. ICV-STZ causes neural damage in the brain by producing free radicals, thereby inducing a state of oxidative stress, impairment of glucose utilization and demyelination (Saxena et al., 2010; Saxena et al., 2008; Saxena et al., 2007; Tota et al., 2010). Spatial memory impairment has been frequently reported in ICV-STZ rats and it takes only a few weeks to induce such impaired spatial memory (Agrawal et al., 2009; Akhtar et al., 2020; Awasthi et al., 2010; Kumar et al., 2017). In the present study, latency time to reach a target platform in the ICV-STZ group was significantly longer than that in the control group (Fig. 1). This suggests a decline in spatial memory in the ICV-STZ rats consistent with previous studies. ICV-STZ rats had significantly lower body weights compared to control rats before MWM tests. However, it has been reported that loss in body weight is not correlated with poor performance in the MWM test (Goodlett et al., 1986; Jett et al., 1997).

Since CSF Aβ1–42 typically reflects its aggregation and deposition in the brain (Fagan et al., 2006), a decrease of Aβ1–42 in the CSF has been observed with the onset and progression of AD in: (1) patients with AD (Hulstaert et al., 1999), (2) patients with sporadic AD (Fagan et al., 2007), (3) autosomal dominant AD mutation carriers (Bateman et al., 2012), and (4) cognitively normal participants (Jia et al., 2024). In this study, although the differences did not reach statistical significance, CSF Aβ1–42 was lower in the ICV-STZ group than that in the control group (Fig. 2B). Inconsistent with our hypothesis, cortex and hippocampus Aβ1–40 and 1–42 were not increased 10 weeks after ICV-STZ injection (Fig. 2A and B). Although more recent findings showed that soluble Aβ oligomers in brain may be the cause of memory loss (Walsh et al., 2002; Walsh and Selkoe, 2004), Aβ in brain has not been proven to be required for the initiation and progression of AD (Yang et al., 2014). While we measured soluble Aβ1–40 and 1–42 using ELISA in this study, earlier studies using immunohistochemical staining reported that ICV-STZ injection increases the number of amyloid plaques (Gupta et al., 2018; Wang et al., 2010). Thus, the results would vary depending on measurement methods. Importantly, there are many causes of cognitive impairment, including neural loss (Knowles et al., 1999; Malek-Ahmadi et al., 2016), neurodegeneration (Aarsland et al., 2021; Wilson et al., 2010), phosphorylated tau protein (Chen et al., 2023; Di et al., 2016), and aging (Han et al., 2022; Murman, 2015). That being said, since these factors were not directly tested in this study, further studies are warranted to clarify the mechanisms underlying the decline of spatial memory. On the other hand, ICV-STZ injection significantly increased brainstem Aβ1–40, but not Aβ1–42 (Fig. 2A and B), even though the expression patterns in specific brainstem regions were unable to be identified. Various brainstem regions are involved in modulating reflex responses to muscle stimulation regulating ABP (Kumagai et al., 2012; Potts, 2006; Potts and Li, 1998). Thus, cardiovascular control neurons in the brainstem may have been impacted by Aβ in the current study. Nevertheless, the mechanisms underlying the selective increase in Aβ in the brainstem of ICV-STZ rats are not clear. It has been reported that the concentration of Aβ1–40 is approximately ten times more than Aβ1–42 (Siegel et al., 2017) and Aβ1–42 is less soluble than Aβ1–40, making it more prone to aggregation (Hampel et al., 2021; Knowles et al., 2014). Future studies are warranted to comprehensively assess the form of Aβ present (soluble or insoluble) using multiple approaches such as ELISA and immunohistochemical staining.

The association between blood pressure and AD has been highly controversial (de Heus et al., 2019; Guan et al., 2011; Skoog et al., 1996). On the other hand, consistent with earlier study using ICV-STZ rats (Ehlen et al., 2022), baseline MAP under 1 % isoflurane as well as after decerebration were not significantly different between control and ICV-STZ groups (Table. 1). Thus, the rat model used in this study may not significantly affect resting blood pressure.

4.2. Pressor and cardioaccelerator responses to tibial nerve stimulation in ICV-STZ rats

ICV-STZ significantly suppressed the pressor and cardioaccelerator responses to tibial nerve stimulation (Fig. 3). To the best of our knowledge, this is the first study showing that ICV-STZ rats elicits a blunted pressor response to stimulation of peripheral sensory nerves. Although the mechanism underlying the attenuated pressor response to afferent nerve stimulation in ICV-STZ rats remain unknown, such a weakened pressor response may be directly and/or indirectly mediated by Aβ. Muscle contraction stimulates group III and group IV primary sensory fibers in working skeletal muscle. The information from peripheral sensory neurons is projected to the NTS and further to the RVLM located within the medulla oblongata (Person, 1989; Potts et al., 2002), resulting in increased blood pressure. Gamma amino butyric acid (GABA) and glutamate are the main inhibitory and excitatory neurotransmitters, respectively, within these nuclei (Lima-Silveira et al., 2022). A major source of the GABAergic inhibition to premotor RVLM neurons arises from an area immediately caudal to the RVLM, known as the caudal ventrolateral medulla (Schreihofer and Guyenet, 2003). Alteration of the activity of these premotor RVLM neurons has profound effects on sympathetic vasomotor tone (Schreihofer and Guyenet, 2002). It has been reported that Aβ binds to neurons and leads to synaptic loss (Hsieh et al., 2006; Shankar et al., 2007). For example, soluble Aβ1–40 levels in the cortex show a significant correlation with degree of synaptic loss (Lue et al., 1999). Although we did not evaluate synaptic loss in cardiovascular control areas such as the NTS and RVLM, it is likely that synaptic loss did indeed occur within the brainstem caused by Aβ1–40 and 1–42, resulting in neurotransmission deficits. In terms of an indirect pathway, sympathetic activity is negatively regulated by central nitric oxide (NO) whose production is enhanced by Aβ. There is considerable evidence that NO within the NTS affects sympathetic nerve activity and modulates blood pressure and HR (Hirooka et al., 1996; Matsumura et al., 1998; Murphy et al., 2013; Zanzinger et al., 1995). Several studies have demonstrated that microinjection of the NO synthase (NOS) inhibitor NG-monomethyl-l-arginine or NG-nitro-l-arginine methyl ester into the NTS produces a pressor effect (Harada et al., 1993; Smith et al., 2005; Tseng et al., 1996). In addition, in vitro studies showed that Aβ stimulates inducible NOS in astrocytes (Akama and Van Eldik, 2000), oligodendrocytes (Zeng et al., 2005), and PC12 cell (Jang and Surh, 2005). Moreover, ICV Aβ1–42 induces an increase in immunoreactivity of endothelial NOS in the activated astrocyte in the hippocampus (Cho et al., 2005). Given the ICV-STZ group significantly increased brainstem Aβ1–40 (Fig. 2A), it is possible that the blunted cardiovascular responses to tibial nerve stimulation were caused by Aβ-induced increases in NO and/or NOS within brainstem. Further investigation is needed to evaluate whether ICV-STZ injection increases NO and/or NOS within NTS.

4.3. Pressor and cardioaccelerator responses to mechanoreflex and metaboreflex activation in ICV-STZ rats

Increasing evidence suggests that AD is a chronic neurodegenerative disease leading to not only cognitive declines but also decreased somatosensory perception. AD transgenic mice have displayed attenuated olfactory function and increased Aβ deposition in peripheral olfactory sensory neurons (Son et al., 2021). Recent studies from our group and others demonstrated that the mechanosensitive channels TRPV4 (Fukazawa et al., 2023), Piezo1/2 (Copp et al., 2016), and TRPC6 (Ducrocq et al., 2024) are involved in the muscle mechanoreflex. In addition, the molecular mechanisms that evoke the muscle metaboreflex are believed to include TRPV1 (Mizuno et al., 2011; Smith et al., 2010), purinergic 2× receptors (McCord et al., 2010), bradykinin B2 receptors (Pan et al., 1985), and acid-sensing ion channels (Ducrocq et al., 2020). Based on these findings, we hypothesized that the progression of AD as well as increased Aβ concentrations in peripheral neurons would cause at least some impairment of primary somatosensory perception by decreasing mechano- and metabo-receptor sensitivity. Even though the integrated pressor response to passive stretch in the ICV-STZ group tended to be lower than that in the control group (Fig. 4F), the pressor and cardioaccelerator responses to passive stretch and capsaicin injection were largely not suppressed in ICV-STZ rats (Figs. 4 and 5). These results are consistent with earlier study showing that individuals with early-stage AD exhibited cardiovascular responses similar to those of nondemented controls (Billinger et al., 2011). Furthermore, plasma Aβ1–40 and 1–42 were not increased in the ICV-STZ group in this study (Fig. 2). Thus, plasma Aβ concentration may not have been high enough to affect the sensitivity of peripheral sensory neurons responsible for the muscle metaboreflex and mechanoreflex. The reasons for the discrepancies among maneuvers (tibial nerve stimulation, passive stretch and capsaicin injection) are not readily clear. The tibial nerve stimulation maneuver used in this study directly and fully activates both mechano- and metabo-sensitive afferent nerve fibers simultaneously (Estrada et al., 2023) while passive muscle stretch (mechano-sensitive fibers) is a more selective physiological stimulus, and exogenous capsaicin (metabo-sensitive fibers) selectively stimulates TRPV1. Based on the results, it is our contention that simultaneous activation of both groups of fibers is requisite to elicit the attenuation in responsiveness observed in ICV-STZ rats but does not manifest when the afferents are stimulated in isolation. Although speculative, this may indicate a change in the integrative relationship between the sensory inputs such that they are inhibitory in nature in ICV-STZ rats.

Our results may shed light on the mechanisms underlying the impact of AD on blood pressure regulation as the effects of AD on blood pressure regulation remain controversial. The blunted pressor response to tibial stimulation in ICV-STZ rats implies an impaired reflexive sympathetic outflow in AD. In fact, this supports an earlier study showing that sympathetic outflow in response to hypotension induced by sodium nitroprusside was blunted in ICV-STZ rats (Ehlen et al., 2022). Further studies are needed since we did not directly assess sympathetic nerve activity. Nevertheless, our results may contribute to understanding the mechanisms underlying the blunted sympathetic responses observed in neurodegenerative diseases such as AD or Parkinson’s disease (Jensen-Dahm et al., 2015; Joseph et al., 2017; Sabino-Carvalho et al., 2021).

4.4. Methodological considerations

We acknowledge several limitations. First, consistent with an earlier study (Chen et al., 2013), cognitive impairment was observed in ICV-STZ group (Fig. 1). However, the dose-response relationship between STZ and AD development as well as the phase dependent alterations in cognitive function and neurochemical changes after STZ injection (Salkovic-Petrisic et al., 2013) remain unknown. In addition, the results might vary if the animals were tested at an earlier time point (i.e., 3–4 weeks after STZ injection) and/or received bilateral STZ injection as in previous studies (Chen et al., 2013; Gupta et al., 2018). We also cannot rule out the possibility that the complete AD phenotype may manifest differently depending on the species [i.e., rats used in the current study vs. mice used in the previous study (Chen et al., 2013)]. Second, in this study, only male rats were examined. Male rats were used in this study to facilitate comparison with the majority of previous reports using male rats only. Thus, results may not be applicable to female rats. Sex differences have been reported to exist in cognitive function and hippocampus Aβ levels in ICV-STZ rats (Bao et al., 2017). Future studies in female rats are needed and warranted. Third, electrical tibial nerve stimulation activated not only group III and IV sensory neurons but also group I and II muscle afferents as well as α-motor neurons (Harms et al., 2016; McCallister et al., 1986). Even though it has been reported that stimulation of group I and II afferents has no reflex effect on cardiovascular response regulation (Hodgson and Matthews, 1968; Waldrop et al., 1984), it might be difficult to completely exclude the possibility that group I and II muscle afferents played a role in the resultant pressor and heart rate responses to tibial nerve stimulation. That being acknowledged, the finding remains that the pressor and cardioaccelerator responses to tibial nerve stimulation were significantly blunted in ICV-STZ rats suggesting the presence of functional impairment in skeletal muscle peripheral sensory neurons. It is important to note, however, electrical tibial nerve stimulation does not necessarily mimic the EPR but instead represents an activation of group III and IV afferent neurons in skeletal muscle. Therefore, the contribution of the EPR to the cardiovascular response to exercise in ICV-STZ rats remains unclear. Fourth, capsaicin, an exogenous substance, was used to activate thin-fiber muscle afferents expressing TRPV1 in this study. Additional studies are warranted to verify the response of TRPV1 to endogenously produced metabolites such as protons (Caterina and Julius, 2001), acid (Tominaga et al., 1998) and heat (Caterina et al., 1997). Lastly, we observed that Aβ1–40 was elevated in the brainstem, but as it was measured in the entire brainstem, we were unable to identify which nuclei in the brainstem were involved.

In conclusion, blunted cardiovascular responses to electrical stimulation of muscle afferents was observed in ICV-STZ rats. These findings suggest that the cardiovascular responsiveness to simultaneous activation of mechano- and metabo-sensitive peripheral muscle afferents is weakened in ICV-STZ rats but does not manifest when these afferent populations are stimulated in isolation.

Funding sources

This work was supported by National Heart, Lung, and Blood Institute (R01HL-151632; to M.M.), JSPS KAKENHI (20H04083 to N. H.), the Southwestern School of Health Professions Interdisciplinary Research Grant Program (to H.Y. and M.M.), and the Jere H. Mitchell, M.D. Distinguished Professorship in Clinical Research (to S.A.S.)

Abbreviations:

ABP

arterial blood pressure

AD

Alzheimer’s disease

ANOVA

analysis of variance

Aβ

amyloid β

CSF

cerebrospinal fluid

ECGs

electrocardiograph signal

EPR

exercise pressor reflex

GABA

gamma amino butyric acid

GLUT

glucose transporter

HR

heart rate

ICV

intracerebroventricular

MT

motor threshold

MWM

Morris Water Mase

NO

nitric oxide

NOS

nitric oxide synthase

NTS

nucleus tractus solitarius

RVLM

rostral ventrolateral medulla

SD

Sprague-Dawley

STZ

streptozotocin

Footnotes

☆

This article is part of a Special issue entitled: ‘Exercise and the Autonomic Nervous System’ published in Autonomic Neuroscience: Basic and Clinical.

CRediT authorship contribution statement

Ayumi Fukazawa: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Formal analysis, Data curation. Norio Hotta: Writing – review & editing, Writing – original draft, Validation, Methodology, Investigation, Funding acquisition, Formal analysis, Data curation. Hoda Yeganehjoo: Writing – review & editing, Validation, Funding acquisition, Formal analysis, Data curation. Amane Hori: Writing – review & editing, Validation. Han-Kyul Kim: Writing – review & editing, Validation. Gary A. Iwamoto: Writing – review & editing, Validation, Supervision. Scott A. Smith: Writing – review & editing, Validation, Supervision, Funding acquisition. Wanpen Vongpatanasin: Writing – review & editing, Validation, Supervision. Masaki Mizuno: Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Funding acquisition, Formal analysis, Conceptualization.

Declaration of competing interest

The authors declare that they have no competing interests.

Data availability

The data supporting the present findings are available from the corresponding author upon reasonable request.

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Associated Data

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Data Availability Statement

The data supporting the present findings are available from the corresponding author upon reasonable request.

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