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Brain & Heart A mini-review on heart-brain communication

markers in the ICNS, but the molecular signaling between neuronal somata. Despite the occasional expression of
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heart and brain has yet to be deciphered. Heartbeat-evoked vesicular glutamate transporter 2, GABAergic transmission
potentials (HEPs), which are brain electrical potentials has not been verified in the ICNS thus far.
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arising from cardiac activity, offer an overview of the A computational modeling of the vagus nerve-ICNS
physiological crosstalk between brain and heart, but the communication postulated that signals from vagal efferent
molecular or hormonal implications of these physiological flow to ICNS, resulting in the release of acetylcholine from
potentials remain unknown. In this review, we highlight ICNS that eventually inhibit the oscillatory firing of the
the role of intrinsic cardiac ganglia (ICNS) as a potential sinoatrial node. However, intrinsic cardiac ganglia are
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relay center for heart-brain communication and discuss able to sustain beat-to-beat cardiac indices in the absence of
the putative link between ICNS and HEP, which reflect the central stimulation, a property that makes ICNS important
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cortical response to the signals originating from the heart. players in cardioprotection. The mechanism underlying this
cardioprotective role involves significantly increased release
2. Intrinsic cardiac ganglia during of acetylcholine from post-ganglionic parasympathetic
embryogenesis neurons, which leads to classical ischemic conditioning.
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Neural crest cells migrate to the developing heart in This suggests that a feedback signal from the heart to the
the 5 week of gestation and later give rise to different brain direct or indirect remains largely unexplored.
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types of neurons including sensory, sympathetic, and 4. Molecular pathways in ICNS
parasympathetic neurons. The eight distinct groups of
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cardiac ganglia at the same anatomical position that would Cholinergic activity in ICNS involves activation of post-
later be identified at the location of intrinsic cardiac ganglia junctional M2 muscarinic receptors, coupled to Gα i
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become distinguishable on the 21 day of gestation in protein which results in negative dromotropic responses.
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rodents, with the exception of ganglia located in the aortic Most sympathetic activity in the heart originates in the
region which are present until the 18 day of gestation and stellate ganglia from the intrathoracic extrinsic cardiac
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disappear afterward. Postnatal development of cardiac ganglia, prompting the release of norepinephrine (NE),
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ganglia in rodent models occurs in the 1 month, during but the cholinergic ICNS possess an integrative network
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which a great number of tyrosine hydroxylase (TH)- and which has sensitive neurons and interneurons that also
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protein gene product 9.5 -rich neurons are detected, release NE. In addition to the expression of noradrenergic
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differentiating into neurons with microtubule-associated neurotransmitters, the noradrenergic trophic factors such
protein-, neuropeptide-Y (NPY)- and acetylcholine as tropomyosin-related kinase A and p75 neurotrophin
transferase (ChAT)-positive neurons. However, evidence receptors are also detected in the ICNS, reflecting both
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suggests that cardiac neurons, especially those serving the cholinergic and adrenergic nature of these neurons, even
conduction system, do not necessarily arise from the neural though instances of colocalization of these markers are
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crest. This finding opens the arena for active exploration occasional. While the exact molecular mechanisms of
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of the origin of non-neural crest neurons. heart-brain communication remain to be elucidated,
this communication is putatively underpinned by the
3. Anatomical aspects and biochemical involvement of M2 and NE receptors, which act through
pathway of heart-brain communication G protein-coupled receptor (GPCR) signaling. Expression
of neuropeptides such as NPY, dynorphine B, substance P,
An anatomical projection of ICNS to vagal ganglia has been and nitric oxide synthase in ICNS highlights the presence
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characterized using a zebrafish model, where expression of phosphatidyl inositol 3 kinase and GPCR signaling
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of TH, ChAT, and vasoactive intestinal peptide (VIP) were pathways in ICNS (Figure 1). However, their exact
detected. TH is a rate-limiting enzyme in the production molecular mechanism and cellular outcomes in intrinsic
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of catecholamines and plays a crucial role in dopamine cardiac ganglia remain to be elucidated. Substance P
synthesis. The release of catecholamines through specially has different roles in cardiac modeling following
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neurohumoral response influences the depolarization of acute and chronic ischemia, where it exerts positive
the sinoatrial node, thereby influencing the heart rhythm. effects in the acute phase but adversely affects myocardial
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The ChAT specifies parasympathetic innervation, while remodeling in the chronic phase. Despite the presence of
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VIP is known to be released from intrinsic and extrinsic these neuropeptides, surprisingly, cholinergic somata are
cardiac nerves, in addition to the vagus nerve, and devoid of the functions for storage and vesicular release,
modulate heart rhythm. Other neurotransmitters have due to the lack of vesicular monoamine transporter
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also been identified in ICNS with a predominance of NPY protein, a feature that distinctly differentiates them from
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and cocaine and amphetamine-regulated transcript in the the typical parasympathetic neurons.
Volume 2 Issue 2 (2024) 2 doi: 10.36922/bh.2901