Post-occlusive reactive hyperemia (PORH) is a classical probe of microvascular function, yet its assessment remains largely based on amplitude-derived indices that do not capture the temporal organization of vascular regulation. Photoplethysmography (PPG), widely used in clinical and wearable technologies, offers a practical platform for nonlinear characterization of PORH. Twelve healthy adults underwent a standardized PORH protocol (10 min baseline, 5 min suprasystolic occlusion, 10 min reperfusion) with bilateral reflective green-light PPG. Pulse amplitude, detrended fluctuation analysis (global DFA α exponent), and multiscale entropy (Complexity Index, CI) were computed in 5 min epochs. Occlusion nearly abolished pulsatility in the test limb but produced only modest changes in fractal structure, as α decreased minimally despite near-zero flow. In contrast, CI showed a marked collapse, indicating loss of multiscale organization. During reperfusion, α exhibited a trend toward increased fractal persistence, whereas CI recovered only partially. Contralateral responses were small and detectable mainly through subtle reductions in α during occlusion and consistently higher CI compared with the test limb. These findings indicate that occlusion disrupts multiscale complexity without eliminating fractal persistence, whereas reperfusion restores correlation structure and only partially re-establishes dynamical richness. Overall, DFA and MSE reveal nonlinear features of PORH that are not captured by conventional amplitude-based metrics, extending the physiological interpretation of microvascular responses using widely available PPG technology.

The venoarteriolar reflex (VAR) is a peripheral vascular response that limits edema formation in dependent limbs. Despite its physiological relevance, it is rarely addressed in teaching laboratories. The author describes a simple, low-cost protocol that uses photoplethysmography (PPG) and basic postural changes to demonstrate the VAR in real time. In most classroom sessions, a reduction in PPG amplitude is observed during limb dependency and rapid recovery when the limb is returned to heart level. These observations provide a basis for discussing hydrostatic effect, Starling's forces, and myogenic mechanisms of vascular regulation. Because PPG reflects skin blood flow, the protocol also invites links to autonomic and endocrine physiology. Requiring minimal equipment and preparation, this demonstration offers an accessible and engaging tool for physiology education. This accessible and engaging protocol helps students integrate theoretical and experimental learning in vascular physiology.NEW & NOTEWORTHY This article presents a simple classroom demonstration of the venoarteriolar reflex (VAR) using photoplethysmography and limb positioning. This low-cost protocol allows students to visualize vascular regulation in real time and stimulates discussion of hydrostatic effect, myogenic activity, and edema prevention. Accessible and engaging, it offers instructors an easy way to connect theoretical principles with direct experimental observation.

Venous perfusion plays a crucial role in vascular health, yet functional assessment of superficial veins remains limited. Near-infrared reflectance imaging (NIRI) devices, commonly used for vein visualization, may offer untapped potential in this context. We investigated whether texture analysis (TA) applied to NIRI-based vein finder images can detect dynamic changes in superficial venous structure during reactive hyperemia. Fourteen healthy adults underwent a suprasystolic occlusion protocol, with real-time images acquired from the hand dorsum. From defined regions of interest, we extracted classical texture parameters (e.g., contrast, correlation, entropy, energy, fractal dimension, and lacunarity) and vein width. While vein width significantly increased during occlusion (p < 0.001), most individual texture parameters remained stable. Notably, correlation increased during occlusion (p = 0.023), and lacunarity decreased during recovery (p = 0.024). We developed composite indices combining texture and morphological features. Entropy-to-width and correlation-to-width ratios decreased during occlusion (p < 0.001), while total entropic content rose (p < 0.001). A modest increase in the correlation-to-entropy ratio during recovery (p = 0.026) suggested delayed reorganization of venous texture. These findings indicate that TA of vein finder images captures functional vascular responses beyond morphology alone. Composite parameters enhance sensitivity and may support the development of non-invasive, low-cost tools for assessing venous function.

Post-occlusive reactive hyperemia (PORH) is widely used to assess microvascular reactivity, but its systemic impact on contralateral neurovascular function remains unclear. This study quantified bilateral synchrony and asymmetry of cutaneous signals during unilateral PORH in healthy subjects using a novel multidimensional framework of inter-limb coherence. Twelve young adults underwent a standard suprasystolic occlusion (5 min at 200 mmHg) on the upper limb, while photoplethysmography (PPG), skin temperature, and electrodermal activity (EDA) were recorded bilaterally in the fingers. Coherence was characterized by profile similarity (Cross-Signal Similarity Index, CSSI), temporal lag (τ*), magnitude asymmetry (Bilateral Magnitude Difference Index, BDMI), directional concordance (Signal Direction Index, SDI; Directional Concordance Index, DCI), and integrated indices (IBIL, IBIS). At baseline, all signals showed high bilateral synchrony (CSSI ≈ 0.9; τ* < 20 ms). Occlusion markedly reduced CSSI for blood flow (0.89 to 0.07, p = 0.002) and temperature (0.93 to −0.03, p = 0.06), while EDA coherence remained preserved (0.95 to 0.82). Integrated indices decreased significantly (IBIL 0.84 to 0.17, p = 0.005; IBIS 0.84 to 0.18, p = 0.004) and recovered only partially during hyperemia (IBIL 0.20, p = 0.003). Directional concordance was heterogeneous: during hyperemia, 9 of 12 subjects showed concordant EDA changes but only 7 of 12 for perfusion. BDMI was largest for perfusion (≈0.8), moderate for temperature (≈0.5), and minimal for EDA (≈0.3). Unilateral PORH thus induces a marked loss of bilateral coherence in microvascular signals, whereas sympathetic-driven responses remain strongly synchronized. This dissociation reveals that occlusion evokes systemic autonomic adjustments beyond local hemodynamics. The proposed framework captures hidden aspects of neurovascular integration and may provide new markers for autonomic imbalance or perfusion asymmetry.

Photoplethysmography (PPG) is a non-invasive optical technique that quantifies blood volume pulsations and enables assessment of skin microvascular dynamics during vascular challenges. Its complex waveform can be decomposed by wavelet transform (WT) into physiological frequency bands reflecting cardiac, respiratory, myogenic, neurogenic, endothelial NO-dependent and endothelial NO-independent activity. Spectral activity may be expressed as either absolute power or relative contribution, which can capture different aspects of microvascular regulation. This study compared both metrics of PPG signals during post-occlusive reactive hyperemia (PORH). PPG was recorded bilaterally in twelve healthy adults (21.6 ± 1.9 years) during a 10-min baseline, 5-min occlusion, and 10-min recovery. Spectral power and percent contribution were calculated for each band and phase using nonparametric statistics (p < 0.05). Occlusion markedly suppressed higher-frequency oscillations (cardiac, respiratory, myogenic, neurogenic) while enhancing endothelial activity. Hyperemia produced a rebound of respiratory and endothelial oscillations above baseline. In the contralateral limb, occlusion induced a milder perfusion decrease, consistent with sympathetic vasoconstriction. Correlations between absolute and relative metrics were strong for cardiac, respiratory, and myogenic components (ρ > 0.80, p < 0.01), but weak or absent for endothelial bands. Absolute power primarily reflected perfusion magnitude, whereas relative contribution represented spectral redistribution among regulatory mechanisms. These metrics are complementary yet non-equivalent, underscoring the need for methodological consistency in the physiological interpretation of wavelet-derived PPG analyses.

Coffee intake is increasingly recognized as a life-style factor associated with the preservation of health, but there is still a debate on the relative effects of caffeinated and decaffeinated coffee. We now tested how the regular drinking of caffeinated and decaffeinated coffee for 3 weeks impacted on the behavior of male and female adult mice. Males drinking caffeinated coffee displayed statistically significant lower weight gain, increased sensorimotor coordination, greater motivation in the splash test, more struggling in the forced swimming test, faster onset of nest building, more marble burying and greater sociability. Females drinking caffeinated coffee displayed statistically significant increased hierarchy fighting, greater self-care and motivation in the splash test and faster onset of nest building. A post-hoc two-way ANOVA revealed sex-differences in the effects of caffeinated coffee (p values for interaction between the effect of caffeinated coffee and sex) on the hierarchy in the tube test (p = 0.044; dominance), in the time socializing (p = 0.044) and in the latency to grooming (p = 0.048; selfcare), but not in the marble burying test (p = 0.089). Intake of decaffeinated coffee was devoid of effects in males and females. Since caffeine targets adenosine receptors, we verified that caffeinated but not decaffeinated coffee intake increased the density of adenosine A1 receptors (A1R) and increased A1R-mediated tonic inhibition of synaptic transmission in the dorsolateral striatum and ventral but not dorsal hippocampus, the effects being more evident in the ventral hippocampus of females and striatum of males. In contrast, caffeinated and decaffeinated coffee both ameliorated the antioxidant status in the frontal cortex. It is concluded that caffeinated coffee increases A1R-mediated inhibition in mood-related areas bolstering wellbeing of both males and females, with increased sociability in males and hierarchy struggling and self-care in females.

The venoarteriolar reflex (VAR) is described as a vasoconstriction occurring in response to an increase in venous transmural pressure. Its underlying mechanisms are still not clarified, particularly the neural pathway that supposedly evokes this reflex. In addition, recent studies have shown that the postural maneuvers that evoke VAR also produce a decrease in contralateral perfusion, which is also poorly understood. Our study aimed to explore the contralateral response to unilateral upper limb dependency and its underlying mechanisms. Fifteen young, healthy subjects (24.1 ± 5.8 y.o.) participated in this study after giving informed consent. While seated, subjects remained for 7 min with both arms at heart level (baseline), after which a random hand was placed 40 cm below the heart level for 5 min (dependency) before resuming the initial position for another 7 min (recovery). Skin perfusion was assessed bilaterally with photoplethysmography, and electrodermal activity (EDA) was assessed in the contralateral hand. During hand dependency, perfusion decreased significantly in both limbs, although it was more pronounced in the dependent limb, corroborating previous reports that unilateral limb dependency evokes a decrease in contralateral perfusion. Transient EDA peaks were detected in the first seconds of the dependency and recovery phases. These results support the participation of the sympathetic nervous system as a mechanism regulating contralateral perfusion during unilateral limb dependency. This sympathetic activation is probably attributed to the postural changes themselves and is likely not related to the VAR.

A combination of Δ9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD) at non-psychoactive doses was previously demonstrated to reduce cognitive decline in APP/PS1 mice, an animal model of Alzheimer's disease (AD). However, the neurobiological substrates underlying these therapeutic properties of Δ9-THC and CBD are not fully understood. Considering that dysregulation of glutamatergic activity contributes to cognitive impairment in AD, the present study evaluates the hypothesis that the combination of these two natural cannabinoids might reverse the alterations in glutamate dynamics within the hippocampus of this animal model of AD. Interestingly, our findings reveal that chronic treatment with Δ9-THC and CBD, but not with any of them alone, reduces extracellular glutamate levels and the basal excitability of the hippocampus in APP/PS1 mice. These effects are not related to significant changes in the function and structure of glutamate synapses, as no relevant changes in synaptic plasticity, glutamate signaling or in the levels of key components of these synapses were observed in cannabinoid-treated mice. Our data instead indicate that these cannabinoid effects are associated with the control of glutamate uptake and/or to the regulation of the hippocampal network. Taken together, these results support the potential therapeutic properties of combining these natural cannabinoids against the excitotoxicity that occurs in AD brains.

Caffeic acid is a polyphenolic compound present in a vast array of dietary components. We previously showed that caffeic acid reduces the burden of brain ischemia joining evidence by others that it can attenuate different brain diseases. However, it is unknown if caffeic acid affects information processing in neuronal networks. Thus, we now used electrophysiological recordings in mouse hippocampal slices to test if caffeic acid directly affected synaptic transmission, plasticity and dysfunction caused by oxygen-glucose deprivation (OGD), an in vitro ischemia model. Caffeic acid (1-10 mu M) was devoid of effect on synaptic transmission and paired-pulse facili-tation in Schaffer collaterals-CA1 pyramidal synapses. Also, the magnitude of either hippocampal long-term potentiation (LTP) or the subsequent depotentiation were not significantly modified by 10 mu M caffeic acid. However, caffeic acid (10 mu M) increased the recovery of synaptic transmission upon re-oxygenation following 7 min of OGD. Furthermore, caffeic acid (10 mu M) also recovered plasticity after OGD, as heralded by the increased magnitude of LTP after exposure. These findings show that caffeic acid does not directly affect synaptic trans-mission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of caffeic acid may allow the design of hitherto unrecognized novel neu-roprotective strategies.

Increased ATP release and its extracellular catabolism through CD73 (ecto-5′-nucleotidase) lead to the overactivation of adenosine A2A receptors (A2AR), which occurs in different brain disorders. A2AR blockade blunts mood and memory dysfunction caused by repeated stress, but it is unknown if increased ATP release coupled to CD73-mediated formation of extracellular adenosine is responsible for A2AR overactivation upon repeated stress. This was now investigated in adult rats subject to repeated stress for 14 consecutive days. Frontocortical and hippocampal synaptosomes from stressed rats displayed an increased release of ATP upon depolarization, coupled to an increased density of vesicular nucleotide transporters and of CD73. The continuous intracerebroventricular delivery of the CD73 inhibitor α,β-methylene ADP (AOPCP, 100 μM) during restraint stress attenuated mood and memory dysfunction. Slice electrophysiological recordings showed that restraint stress decreased long-term potentiation both in prefrontocortical layer II/III–layer V synapses and in hippocampal Schaffer fibers-CA1 pyramid synapses, which was prevented by AOPCP, an effect occluded by adenosine deaminase and by the A2AR antagonist SCH58261. These results indicate that increased synaptic ATP release coupled to CD73-mediated formation of extracellular adenosine contributes to mood and memory dysfunction triggered by repeated restraint stress. This prompts considering interventions decreasing ATP release and CD73 activity as novel strategies to mitigate the burden of repeated stress.

Fear learning is essential to survival, but traumatic events may lead to abnormal fear consolidation and overgeneralization, triggering fear responses in safe environments, as occurs in post-traumatic stress disorder (PTSD). Adenosine A2A receptors (A2AR) control emotional memory and fear conditioning, but it is not known if they affect the consolidation and generalization of fear, which was now investigated. We now report that A2AR blockade through systemic administration of the A2AR antagonist SCH58261 immediately after contextual fear conditioning (within the consolidation window), accelerated fear generalization. Conversely, A2AR activation with CGS21680 decreased fear generalization. Ex vivo electrophysiological recordings of field excitatory post-synaptic potentials (fEPSPs) in CA3-CA1 synapses and of population spikes in the lateral amygdala (LA), showed that the effect of SCH58261 is associated with a reversion of fear conditioning-induced decrease of long-term potentiation (LTP) in the dorsal hippocampus (DH) and with increased amplitude of LA LTP in conditioned animals. These data suggest that A2AR are engaged during contextual fear consolidation, controlling long-term potentiation mechanisms in both DH and LA during fear consolidation, impacting on fear generalization; this supports targeting A2AR during fear consolidation to control aberrant fear processing in PTSD and other fear-related disorders.

Alzheimer's disease (AD), which predominantly affects women, involves at its onset a metabolic deregulation associated with a synaptic failure. Here, we performed a behavioral, neurophysiological and neurochemical characterization of 9-month-old female APPswe/PS1dE9 (APP/PS1) mice as a model of early AD. These animals showed learning and memory deficits in the Morris water maze, increased thigmotaxis and anxiety-like behavior and showed signs of fear generalization. Long-term potentiation (LTP) was decreased in the prefrontal cortex (PFC), but not in the CA1 hippocampus or amygdala. This was associated with a decreased density of sirtuin-1 in cerebrocortical synaptosomes and a decreased density of sirtuin-1 and sestrin-2 in total cerebrocortical extracts, without alterations of sirtuin-3 levels or of synaptic markers (syntaxin, synaptophysin, SNAP25, PSD95). However, activation of sirtuin-1 did not affect or recover PFC-LTP deficit in APP/PS1 female mice; instead, inhibition of sirtuin-1 increased PFC-LTP magnitude. It is concluded that mood and memory dysfunction in 9-month-old female APP/PS1 mice is associated with a parallel decrease in synaptic plasticity and in synaptic sirtuin-1 levels in the prefrontal cortex, although sirtiun1 activation failed to restore abnormal cortical plasticity.

Following the publication of [...]

The intracerebroventricular (icv) injection of amyloid peptides (Aβ) models Alzheimer’s disease (AD) in mice, as typified by the onset within 15 days of deficits of memory and of hippocampal long-term potentiation (LTP) that are prevented by the blockade of adenosine A2A receptors (A2AR). Since A2AR overfunction is sufficient to trigger memory deficits, we tested if A2AR were upregulated in hippocampal synapses before the onset of memory deficits to support the hypothesis that A2AR overfunction could be a trigger of AD. Six to eight days after Aβ-icv injection, mice displayed no alterations of hippocampal dependent memory; however, they presented an increased excitability of hippocampal synapses, a slight increase in LTP magnitude in Schaffer fiber-CA1 pyramid synapses and an increased density of A2AR in hippocampal synapses. A2AR blockade with SCH58261 (50 nM) normalized excitability and LTP in hippocampal slices from mice sacrificed 7–8 days after Aβ-icv injection. Fifteen days after Aβ-icv injection, mice displayed evident deficits of hippocampal-dependent memory deterioration, with reduced hippocampal CA1 LTP but no hyperexcitability and a sustained increase in synaptic A2AR, which blockade restored LTP magnitude. This shows that the upregulation of synaptic A2AR precedes the onset of deterioration of memory and of hippocampal synaptic plasticity, supporting the hypothesis that the overfunction of synaptic A2AR could be a trigger of memory deterioration in AD.

Adenosine receptors mainly control synaptic function, and excessive activation of adenosine receptors may worsen the onset of many neurological disorders. Accordingly, the regular intake of moderate doses of caffeine antagonizes adenosine receptors and affords robust neuroprotection. Although caffeine intake alters brain functional connectivity and multi-omics analyses indicate that caffeine intake modifies synaptic and metabolic processes, it is unclear how caffeine intake affects behavior, synaptic plasticity and its modulation by adenosine. We now report that male mice drinking caffeinated water (0.3 g/L) for 2 weeks were behaviorally indistinguishable (locomotion, mood, memory) from control mice (drinking water) and displayed superimposable synaptic plasticity (long-term potentiation) in different brain areas (hippocampus, prefrontal cortex, amygdala). Moreover, there was a general preservation of the efficiency of adenosine A1 and A2A receptors to control synaptic transmission and plasticity, although there was a tendency for lower levels of endogenous adenosine ensuring A1 receptor-mediated inhibition. In spite of similar behavioral and neurophysiological function, caffeine intake increased the energy charge and redox state of cortical synaptosomes. This increased metabolic competence likely involved a putative increase in the glycolytic rate in synapses and a prospective greater astrocyte–synapse lactate shuttling. It was concluded that caffeine intake does not trigger evident alterations of behavior or of synaptic plasticity but increases the metabolic competence of synapses, which might be related with the previously described better ability of animals consuming caffeine to cope with deleterious stimuli triggering brain dysfunction.

Extracellular ATP can be a danger signal, but its role in striatal circuits afflicted in Parkinson’s disease (PD) is unclear and was now investigated. ATP was particularly released at high stimulation intensities from purified striatal nerve terminals of mice, which were endowed with different ATP-P2 receptors (P2R), although P2R antagonists did not alter corticostriatal transmission or plasticity. Instead, ATP was extracellularly catabolized into adenosine through CD73 to activate adenosine A 2A receptors (A 2A R) modulating corticostriatal long-term potentiation (LTP) in mice. In the presymptomatic phase of a 6-hydroxydopamine rat model of PD, ATP release from striatal nerve terminals was increased and was responsible for a greater impact of CD73 and A 2A R on corticostriatal LTP. These observations identify increased ATP release and ATP-derived formation of extracellular adenosine bolstering A 2A R activation as a key pathway responsible for abnormal synaptic plasticity in circuits involved in the onset of PD motor symptoms. The translation of these findings to humans prompts extending the use of A 2A R antagonists from only co-adjuvants of motor control in Parkinsonian patients to neuroprotective drugs delaying the onset of motor symptoms.

Ginkgo biloba is the oldest living tree species in the world. Despite less than encouraging clinical results, extracts from its leaves are among the most used herbal preparations in the prevention and treatment of cardiovascular diseases. Most data on the efficacy of Ginkgo biloba on cardiovascular disease is from clinical studies, with few results from healthy subjects. This paper aims to provide a comprehensive review of the mechanisms underlying the known beneficial cardiovascular activities of Ginkgo biloba. It displays myocardial suppressant and vasorelaxant activities ex vivo, potentiating endothelial-dependent and -independent pathways. It improves perfusion in different vascular beds, namely ocular, cochlear, cutaneous, cerebral, and coronary. Although scarce, evidence suggests that Ginkgo biloba displays a heterogeneous effect on tissue perfusion which is dependent on the individual elimination pathways. It displays an acceptable safety profile, with most reported adverse reactions constituting rare occurrences. Collectively, Ginkgo biloba positively impacts cardiovascular physiology, improving hemodynamics and organ perfusion. In the future, better controlled clinical studies should be performed in order to identify the target populations who may benefit the most from pharmacotherapeutic interventions involving Ginkgo biloba.

Alzheimer's disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple transgenic male mice modeling AD (3xTg-AD) at Zeitgeber 04 (ZT-4, inactive phase) and ZT-16 (active phase). Using the Morris water maze test to minimize the influence of circadian-associated locomotor activity, we observed a circadian variation in hippocampus-dependent learning performance in non-Tg mice, which was impaired in 3xTg-AD mice. 3xTg-AD mice also displayed a lack of circadian variation of their performance in the reversal spatial learning task. Additionally, the amplitude of hippocampal long-term potentiation also exhibited a circadian profile in non-Tg mice, which was not observed in 3xTg-AD mice. Moreover, cerebral cortical synaptosomes of non-Tg mice also displayed a circadian variation of FCCP-stimulated oxygen consumption as well as in mitochondrial calcium retention that were blunted in 3xTg-AD mice. In sum, this multidimensional study shows that the ability to maintain a circadian oscillation in brain behavior, synaptic plasticity, and synaptic mitochondria function are simultaneously impaired in 3xTg-AD mice, highlighting the effects of circadian misalignment in AD.

Lemongrass (Cymbopogon citratus (DC) Stapf) is a herb commonly used in folk medicine for many purposes. However, its anti-hypertensive potential has not yet been thoroughly studied. This paper reviews the anti-hypertensive effects of both lemongrass and its main compound citral in in vitro, ex vivo, preclinical and clinical studies. Lemongrass essential oil contains terpenes and their derivatives, whereas extracts contain different classes of polyphenols. Both citral and lemongrass display vasorelaxant activity ex vivo, acting by the promotion of endothelial nitric oxide/prostanoids secretion together with the blockage of calcium channels in the vascular smooth muscle. Citral also displays a negative chronotrope effect, probably due to a centrally mediated enhancement of parasympathetic activity. In both healthy and hypertensive animals, the acute administration of lemongrass results in a decrease in blood pressure, sometimes accompanied by a compensatory increase in heart rate. Similarly, in healthy and hypertensive human subjects, the consumption of lemongrass tea decreases blood pressure. Additionally, a weak/moderate diuretic activity has also been reported in animals and humans, although the mechanisms of action remain elusive. Future preclinical studies are necessary to identify other compounds with anti-hypertensive activity and additional pharmacological pathways. Although well tolerated, the safety profile of lemongrass should be better characterized.