Central nervous system neuroplasticity and the sensitization of hypertension

Abstract

The causes of essential hypertension remain an enigma. Interactions between genetic and external factors are generally recognized to act as aetiological mechanisms that trigger the pathogenesis of high blood pressure. However, the questions of which genes and factors are involved, and when and where such interactions occur, remain unresolved. Emerging evidence indicates that the hypertensive response to pressor stimuli, like many other physiological and behavioural adaptations, can become sensitized to particular stimuli. Studies in animal models show that, similarly to other response systems controlled by the brain, hypertensive response sensitization (HTRS) is mediated by neuroplasticity. The brain circuitry involved in HTRS controls the sympathetic nervous system. This Review outlines evidence supporting the phenomenon of HTRS and describes the range of physiological and psychosocial stressors that can produce a sensitized hypertensive state. Also discussed are the cellular and molecular changes in the brain neural network controlling sympathetic tone involved in long-term storage of information relating to stressors, which could serve to maintain a sensitized state. Finally, this Review concludes with a discussion of why a sensitized hypertensive response might previously have been beneficial and increased biological fitness under some environmental conditions and why today it has become a health-related liability.

Key points

  • The aetiology of essential hypertension is still unknown.

  • Emerging evidence has shown that the hypertensive response can undergo sensitization.

  • Hypertensive response sensitization (HTRS) involves neuroplasticity induced by a wide range of physiological and behavioural challenges (stressors) occurring throughout life.

  • The cellular and molecular changes that mediate HTRS are located and maintained in the central neural network that controls sympathetic nervous system activity.

  • The neuroplasticity of the sympathetic nervous system provides adaptive blood pressure control, such that an increased hypertensive response (to physiological or psychosocial stressors) is learned and subsequently remembered.

  • Recognition of HTRS and the centrally mediated mechanisms driving the sensitized state provides a new paradigm for understanding essential hypertension and developing new strategies for its prevention and treatment.

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Fig. 1: The hypothetical role of neuroplasticity and hypertensive response sensitization in the aetiology and progression of essential hypertension.
Fig. 2: A portion of the neural network controlling sympathetic tone and blood pressure.
Fig. 3: Mechanisms involved in hypertensive response sensitization and neuroplasticity.
Fig. 4: How a high-fat diet and obesity might induce hypertensive response sensitization.

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Acknowledgements

The authors thank M. Dennis of the Department of Psychological and Brain Sciences at the University of Iowa for help in preparing the manuscript. The authors’ work described in this Review was supported by US National Institutes of Health (NIH) grants HL14388, MH080241, HL73986, HL84027 and HL139575 (to A.K.J.) and HL98207 (to A.K.J. and B.X.).

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Glossary

Response sensitization

Sensitization is operationally defined and occurs when repeated administration of a stimulus results in an increase in the magnitude of a response.

General adaptation syndrome

A term describing the three predictable stages of behavioural and physiological responses to stressors. The ‘alarm reaction’ stage provides a burst of energy to deal with the onset of a stressor. In the ‘resistance’ stage, the body attempts to overcome or adapt to the stressor. Maintenance of the resistance stage is hypothesized to lead to ‘exhaustion’, with depletion of bodily resources, morbidity and mortality.

Stressor

A threatening or noxious stimulus that produces a stress response and is associated with the state defined as stress (that is, an inferred state or hypothetical construct).

Classical or Pavlovian conditioning

A learning paradigm first developed by the physiologist Ivan Pavlov. A biologically potent stimulus (such as food or an electric shock) is paired with a previously neutral stimulus (such as a tone or light). Pairing produces an association between the two stimuli, such that the neutral stimulus comes to elicit a response similar to that originally produced by a prepotent stimulus.

Limbic system

An extensive set of phylogenetically old, interconnected brain structures located in the rostral part of the nervous system (forebrain). The limbic system was originally identified as a functional system related to emotion. Today, limbic structures are implicated in the control of many physiological, behavioural and cognitive functions.

Lamina terminalis

The single layer of ependymal cells that forms the rostral wall of the third cerebral ventricle. Four structures — the subfornical organ, median preoptic nucleus, the organum vasculosum of the lamina terminalis and the anterior commissure — lie immediately rostral to the lamina terminalis and are often, albeit technically erroneously, commonly referred to as the lamina terminalis.

Neuromodulator

A substance released by neurons that acts to increase or decrease the actions of neurotransmitters. Neuromodulators affect large numbers of neurons by acting in a diffuse paracrine fashion, which is in contrast to the tight coupling between neurons using synaptic neurotransmitters to communicate.

Cytokines

Proteins that are important in autocrine, paracrine and endocrine signalling, particularly in the immune system. Pro-inflammatory cytokines promote inflammation, whereas anti-inflammatory cytokines reduce inflammation. Adipokines are cytokines secreted by adipose tissue.

Long-term potentiation

The strengthening of synapses that results from increased neural activity. Long-term potentiation facilitates synaptic transmission between adjacent neurons.

Operant conditioning

Also known as instrumental conditioning. A type of learning in which a response is modified by positive or negative reinforcement, that is, by association with the presentation of either a reward (such as food) or a punishment (such as electric shock).

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Johnson, A.K., Xue, B. Central nervous system neuroplasticity and the sensitization of hypertension. Nat Rev Nephrol 14, 750–766 (2018). https://doi.org/10.1038/s41581-018-0068-5

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