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Review

Stress in Fish: Neuroendocrine and Neurotransmitter Responses

by
Mingzhe Yuan
1,2,†,
Qian Fang
1,†,
Weiqun Lu
3,
Xubo Wang
1,
Tianwei Hao
4,
Cheong-Meng Chong
5 and
Shan Chen
1,2,*
1
Key Laboratory of Applied Marine Biotechnology, Ningbo University, Ministry of Education, Ningbo 315211, China
2
State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo 315211, China
3
National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
4
Department of Civil and Environmental Engineering, Faculty of Science and Technology, University of Macau, Macau 999078, China
5
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao 999078, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Fishes 2025, 10(7), 307; https://doi.org/10.3390/fishes10070307
Submission received: 21 May 2025 / Revised: 12 June 2025 / Accepted: 17 June 2025 / Published: 27 June 2025
(This article belongs to the Special Issue Stress Physiology in Aquatic Animals)
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Abstract

Farmed fish face persistent challenges arising from diverse environmental factors and human activities, which induce both acute and chronic stress responses, thereby increasing their susceptibility to diseases and mortality. Therefore, it is essential to comprehend the stressors and corresponding stress responses in fish to recognize and mitigate harmful stress during aquaculture practices. In this review, we provide an overview of the various stressors present in aquaculture, along with the resultant alterations in neuroendocrine responses, including the brain–sympathetic–chromaffin cell (BSC) axis, hypothalamus–pituitary–interrenal (HPI) axis, and caudal neurosecretory system (CNSS), as well as neurotransmitter levels within the nervous system, experienced by fish under different types of stress. Fish possess well-developed nervous and endocrine systems that respond to stress, with complex communication networks among these systems demonstrating distributed collaboration. An understanding of the neuroendocrine and neurotransmitter responses to stress may enhance our comprehension of fish stress mechanisms and facilitate the development of an integrated dietary supplementation strategy and improve their resilience against the diverse stresses encountered in aquaculture.
Keywords:
stress; aquaculture; neural responses; neuroendocrine responses; fish
Key Contribution: The paper presents an integrative neuroendocrine framework that connects the stress re-sponses of the BSC axis; HPI axis; CNSS; and neurotransmitter systems in fish. It also re-views the current supplements utilized for stress mitigation via neuroendocrine and neu-rotransmitter regulation. This provides a comprehensive understanding of the stress framework, contributing to the development of potential neuro-modulation strategies aimed at enhancing stress resilience in farmed fish.

Graphical Abstract

1. Introduction

Over the past few decades, the growing demand for fish protein and changes in dietary habits have driven the explosive development of aquaculture [1,2]. However, the growth of aquaculture is constrained by various environmental and husbandry-related stressors, particularly crowding, handling, and environmental fluctuations. These factors induce systemic physiological disruptions in farmed fish, ultimately leading to reduced aquaculture production. While the definition of stress remains a topic of debate, recent literature, widely acknowledged by researchers, suggests that the colloquial use of the term “stress” should be restricted to situations where environmental demands exceed an organism’s natural regulatory capacity and adaptive resources in a maladaptive manner [3,4]. It has been demonstrated that, in response to stress, fish exhibit a series of neural and neuroendocrine reactions aimed at recognizing stressors, alleviating their adverse effects, and maintaining homeostasis [5,6]. Depending on the intensity and duration of the stressor, acute stress can have beneficial effects, while chronic stress typically has detrimental consequences, increasing fish vulnerability to fatal diseases [7]. The terms “acute” and “chronic” are context-dependent and should be defined based on the duration of their physiological consequences in animals [8]. For instance, being caught in a net or escaping from a predator would typically be classified as “acute stress”, whereas overcrowding in a tank or occupying a low position in the social hierarchy would generally be categorized as “chronic stress”. Although existing literature has extensively explored the physiological consequences of stress in fish, such as stress-induced growth impairment [9], reproductive axis dysregulation [10], and osmoregulatory failure [11], research remains fragmented in addressing how stressors systematically influence multiple organ systems, particularly in the context of aquaculture-relevant stressors, and how to leverage their well-developed and complex neural and neuroendocrine regulation for stress mitigation. Therefore, it is crucial to deepen our understanding of the mechanisms underlying neural and neuroendocrine responses when fish cope with stress. This article provides a comprehensive overview of prevalent stressors in aquaculture, as well as the intricate interplay between neural and neuroendocrine responses in fish during periods of stress. It aims to enhance understanding of fish stress and illustrate an integrated adaptation strategy that enhances their resilience against the multifaceted challenges they encounter.

2. Stressors in Aquaculture

Common stressors in aquaculture activities, such as unsuitable temperature (high or low), pH (acidic or alkaline conditions), dissolved oxygen (hypoxia or hyperoxia), microorganisms (pathogenic parasites, bacteria, or viruses), and overcrowding, can be categorized as environmental and anthropogenic stressors based on their sources. These can further be classified into physical, chemical, biological, and procedural stressors (Table 1). Changes in these stressors during the culture period can adversely affect fish behavior, growth, immunity, and reproduction, leading to economic losses for aquaculturists. Oxygen delivery limitations and cardiac failure are recognized as critical factors in sublethal thermal stress [12]; however, stressors rarely occur in isolation. For instance, increases in water temperature not only elevate fish oxygen demand and reduce dissolved oxygen levels, but also enhance the toxicity of harmful substances (e.g., unionized ammonia, toxic microalgae) [13,14], accelerating homeostasis imbalance in fish. Meanwhile, unlike livestock, fish live in water, making it challenging for aquaculturists to detect anomalies promptly. Therefore, stress in aquaculture should not be overlooked, and intensive environmental monitoring and control are essential for sustainable aquaculture practices. However, maintaining an absolutely stable environment free of stressors during farming is impractical. Additionally, fish possess a highly developed and complex neural and neuroendocrine regulatory system that can initiate a series of signaling cascades to address homeostatic threats caused by stress. Understanding the cellular and molecular mechanisms of neural and neuroendocrine responses and their interaction networks during stress may help mitigate the negative effects of stress, improve disease resistance, and develop strategies to regulate the neural and neuroendocrine systems in fish.

3. Neurotransmitters and Neuroendocrine Systems Respond to Stress in Fish

When fish are exposed to stress, the primary stress responses involve neural and neuroendocrine reactions. A perceived threat activates the neural circuits in the brain, which subsequently triggers the downstream endocrine systems and other responsive organs [3,89]. The nervous system employs a variety of neurotransmitters in response to stress (Figure 1). In fish, three major neuroendocrine systems are involved in stress responses: the brain–sympathetic–chromaffin cell (BSC) axis, the hypothalamus–pituitary–interrenal (HPI) axis, and the caudal neurosecretory system (CNSS), each playing distinct roles in stress adaptation (Figure 2). Specifically, the BSC axis rapidly mobilizes energy and enhances cardiovascular function during acute stress through catecholamine release. The HPI axis orchestrates long-term stress adaptation by regulating metabolism, immunity, and osmoregulation via glucocorticoid secretion. Additionally, the CNSS provides complementary regulation by modulating circulating levels of stress-related hormones and cortisol production in response to specific stressors (Table 2).

3.1. Neurotransmitter During Stress

3.1.1. Acetylcholine (ACh)

ACh is a neurotransmitter released by cholinergic neurons and is present in both the peripheral nervous system (PNS) and central nervous system (CNS) of fish [90]. Cholinergic systems in the brain play regulatory roles in various physiological processes, including muscle contraction, autonomic regulation, cognitive function, and stress responses. Cholinergic neurons are characterized by the presence of choline acetyltransferase (ChAT), which facilitates ACh synthesis, and the vesicular acetylcholine transporter (VAChT), which transports ACh into synaptic vesicles. The presynaptic release of ACh from vesicles into the synaptic cleft activates nicotinic and muscarinic ACh receptors (nAChR and mAChR, respectively), followed by degradation via acetylcholinesterase (AChE) into acetate and choline. Choline is subsequently transported back into presynaptic neurons via the high-affinity choline transporter (HACT) [91].
It is widely acknowledged that most stressors lead to a rapid, transient increase in ACh release within the cholinergic system [92,93]. This release may modulate the activation of stress-related signaling pathways. However, depending on the source and intensity of the stressor, ACh levels may decrease under certain conditions following stress exposure [94]. Due to its low concentrations and rapid turnover, measuring ACh levels in the fish brain poses significant challenges. Consequently, it is common practice to evaluate the activity of ACh-related enzymes and the expression of ACh receptors as indirect indicators of cholinergic system responses during stress. Positive correlations have been observed between ACh content and ChAT activity in various fish species, such as common carp (Cyprinus carpio), rainbow trout (Oncorhynchus mykiss), and eel (Anguilla anguilla) [95]. Conversely, the inhibition of AChE expression and activity has been noted under different stress conditions, including heavy metal exposure [96], temperature changes in common carp [97], pesticide exposure in tilapia (Oreochromis mossambicus) [98,99], parasite infestation in killfish (Fundulus parvipinnis) [100], and exposure to underwater electric currents in rainbow trout [101]. Additionally, AChE is widely recognized as a key neurotoxic biomarker reflecting cholinergic responses to various stressors in fish [102]. Reduced AChE activity indicates impaired cholinergic transmission and subsequent ACh accumulation. A study by Jifa et al. (2006) reported no significant inhibition of AChE in the brain of Japanese seabass (Lateolabrax japonicus) exposed to benzo[a]pyrene (BaP) at concentrations of 2 and 20 µg L−1 for 6, 12, and 18 days, suggesting that these concentrations had minimal effects on AChE activity [103]. Furthermore, studies have shown that exposure to low-molecular-weight polycyclic aromatic hydrocarbons (PAHs) does not induce changes or stimulation in AChE activity [104]. Stress has also been reported to upregulate ACh receptor expression in fish [105]. The activation of nAChR can induce anxiolytic-like effects in zebrafish (Danio rerio) [106], while mAChR antagonists can disrupt stress responses caused by organophosphorus exposure [107].

3.1.2. Glutamate (Glu) and Gamma-Aminobutyric Acid (GABA)

Glu and GABA are the principal neurotransmitters in the central nervous system. Both Glu and GABA are synthesized not only in the brain, but also in peripheral tissues and organs [108,109]. Glu primarily functions as an excitatory neurotransmitter, while GABA serves as an inhibitory neurotransmitter. These two substances exhibit opposing yet complementary physiological roles, collectively regulating the normal functioning of the nervous system [110]. Glutamate is synthesized in neurons from intermediates of the glucose-derived tricarboxylic acid cycle and branched-chain amino acids, a process catalyzed by glutaminase using glutamine (Gln) as a precursor. Within neurons, cytoplasmic glutamate is encapsulated into vesicles by vesicular glutamate transporters for subsequent extracellular release. Upon neuronal depolarization and the initiation of signal transduction, these glutamate-containing vesicles are released into the synaptic cleft, where they bind to three types of ionotropic glutamate receptors (iGluRs): N-methyl-D-aspartic acid receptor (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPA), and kainate receptors [111], as well as metabotropic glutamate receptors (mGluRs). Subsequently, glutamate is removed and converted into Gln through the action of glutamine synthetase [112]. The synthesis of GABA is facilitated by the enzymatic action of glutamic acid decarboxylase (GAD), which catalyzes the α-decarboxylation reaction using Glu as a precursor. GABA exerts its effects through GABAA and GABAB receptors, which are classified into two primary categories: ionotropic receptors and metabotropic receptors, respectively [113].
When subjected to stress, maintaining the balance between Glu and GABA is crucial for the physiological adaptation of fish. An imbalance between Glu and GABA can disrupt homeostasis, leading to increased excitotoxicity, which ultimately results in cellular swelling, irreversible neuronal damage, and even cell death [114,115]. It has been reported that glutamic acid effectively alleviates the adverse effects of saline–alkali environments on aquatic organisms such as grass carp (Ctenopharyngodon idella) and tilapia [116,117]. In response to heat stress challenges, rainbow trout activate the glutamate–glutamine metabolic pathway to mitigate oxidative damage caused by elevated temperatures [118]. Notably, under saline–alkali environmental stress conditions, disruption or blockage of the glutamate metabolic pathway directly affects ammonia excretion processes in crucian carp, resulting in nitrogenous waste accumulation within the body, which may ultimately trigger an inflammatory response [119]. In aquatic animals, GABA plays a crucial role in regulating glucose homeostasis during fasting stress [120], alleviating hyperglycemia symptoms, and enhancing the resilience of animals subjected to heat stress [121]. Further research has demonstrated that incorporating GABA into animal feed can significantly increase serum GABA levels while concurrently reducing serum concentrations of glucose and corticosterone hormones in stressful environments, thereby effectively mitigating the stress response [122,123]. In summary, the Glu and GABA systems play an indispensable regulatory role under various environmental stresses.

3.1.3. Catecholamine (CA)

CAs are synthesized in the brain, adrenal medulla (head kidney in fish), and certain sympathetic nerve fibers. These CAs, including dopamine (DA), norepinephrine (NE), and epinephrine (E), are biosynthesized from tyrosine (Tyr). The process begins with hydroxylation catalyzed by tyrosine hydroxylase (TH), converting Tyr into dihydroxyphenylalanine (DOPA). Subsequently, DOPA undergoes decarboxylation mediated by aromatic amino acid decarboxylase (AADC) to produce DA. In some neurons, DA functions directly as a neurotransmitter, while in others, it is further transported into chromaffin granules for additional processing. Within these granules, DA is hydroxylated by dopamine-β-hydroxylase (DbH) to form NE, which is then methylated via a reaction catalyzed by phenylethanol-N-methyl transferase (PNMT) to yield E [124]. The activities of CAs are mediated through their binding to various receptors. Specifically, dopamine receptors are classified into two families: D1-like (encompassing D1 and D5 subtypes) and D2-like (including D2, D3, and D4 subtypes), while adrenergic receptors are categorized into three families: ADRα1 (α1A, α1B, α1D), ADRα2 (α2A, α2B, α2C), and ADRβ (β1, β2, β3), based on their molecular structure and pharmacological properties [125,126]. CAs play a pivotal role in intricate processes such as behavior, movement, emotion, and memory [127,128,129].
When fish and other vertebrates experience stress, they rapidly release CAs to elevate plasma glucose levels, thereby providing essential energy support for the instinctive “fight-or-flight” response [130]. In marine organisms, environmental factors significantly influence stress responses. For example, Harpagifer antarcticus exhibits significant alterations in neurotransmitter levels, including DA and NE, in response to fluctuations in seawater temperature and salinity, highlighting the critical role of stress responses in the adaptation of marine organisms to environmental changes [131]. Zebrafish subjected to acute osmotic pressure changes and hypoxia show marked reductions in NE and E levels within their brains, affecting reproductive signaling processes and revealing the potential impact of stress responses on fish reproductive health [132]. The hypoxia-tolerant tropical fish Pygocentrus nattereri demonstrates notable effects of myocardial NE and E on cardiac function under hypoxic conditions, facilitating its ability to sustain vital activities in low-oxygen environments [133]. Furthermore, E plays a crucial role in regulating energy balance in the livers of chondrichthyan fish, particularly under stressful conditions [134].
In aquaculture practices, the farming environment profoundly influences fish stress responses. Gilthead seabream larvae exposed to adverse conditions such as high-density farming and fasting exhibit significant alterations in DA and NE levels and brain monoamines to adapt to these challenges [135]. Conversely, rainbow trout exposed to low farming densities experience disruptions in brain CA levels, leading to physiological abnormalities such as reduced survival rates, impaired growth and feed efficiency, and dysregulation of immune and inflammatory systems [136]. Additionally, farming density significantly affects CA levels in rainbow trout, underscoring the importance of the farming environment on fish stress responses [136]. Beyond farming density, various environmental factors also influence fish stress responses. For instance, exposure to AlCl3 results in decreased levels of GABA, DA, and NE in zebrafish, while glutamate levels increase [137]. Similarly, adult zebrafish exposed to methamphetamine (METH) exhibit time- and concentration-dependent decreases in brain DA and NE levels, accompanied by increased anxiety-like behavior [138].

3.1.4. Serotonin

The monoamine serotonin, also known as 5-hydroxytryptamine (5-HT), is a major neurotransmitter in both the central nervous system (CNS) and peripheral nervous system (PNS) of fish. It plays a critical role in vasoconstriction [139], hemostasis, intestinal motility [140], and stress responses [141]. The biosynthesis of 5-HT occurs in a two-step process: first, dietary L-tryptophan undergoes hydroxylation catalyzed by tryptophan hydroxylase (Tph) to form 5-hydroxytryptophan (5-HTP), followed by decarboxylation mediated by aromatic amino acid decarboxylase (Aadc) to produce 5-HT. Subsequently, 5-HT is metabolized into 5-hydroxyindole acetic acid (5-HIAA) via the combined actions of monoamine oxidase (Mao) and aldehyde dehydrogenase (Ad) [142]. Additionally, serotonergic neurons can be identified based on the presence of the 5-HT transporter (Sert) and 5-HT receptors.
Numerous studies have demonstrated that stress induces hyperactivity of serotonin metabolism in fish [143,144]. In tilapia and zebrafish, social stress and acute isolation stress lead to reduced levels of 5-HT and increased levels of its metabolite 5-HIAA [145,146,147]. The tryptophan hydroxylase 1a (tph1a) gene was significantly upregulated in the gills of zebrafish following long-term exposure to microplastics and heavy metals [148]. Meanwhile, repeated heat stress and acute ammonia exposure result in significant reductions in brain 5-HT levels and tph1/tph2 expression [149,150]. Acute social stress has been reported to downregulate Mao A gene transcription and enhance 5-HT metabolism in the brains of tilapia [147]. Furthermore, a study on rainbow trout revealed decreased MAO activity in the brainstem and telencephalon but increased activity in the optic tectum and hypothalamus during confinement stress [151].
Serotonin exerts its functions by binding to specific serotonin receptors. In fish, seven families of 5-HT receptors with at least 39 genes have been identified [152]. Many of these receptors respond to various stressors [152,153]. The inhibition of 5-HT receptors has been shown to attenuate stress responses in flatfish [154], salmon [155], tilapia [145], and zebrafish [156], while agonists of 5-HT receptors enhance stress responses in non-stressed fish [157]. Additionally, some agonists of 5-HT receptors, such as buspirone and MK-212, reduce stress-induced behaviors in fish [155,156,158]. Emerging evidence suggests individual variability in sensitivity to serotonin fluctuations within the same species. Fish with divergent stress coping styles, such as proactive versus reactive coping, exhibit differences in 5-HT-related functions. These differences are reflected in generally higher brainstem 5-HT concentrations and lower telencephalic 5-HT activity, as indicated by the ratio of 5-HIAA to 5-HT, in proactive fish compared to reactive ones [159].

3.2. Neuroendocrine Systems During Stress

3.2.1. Brain–Sympathetic–Chromaffin Cell (BSC) Axis

The autonomic nervous system provides the most immediate “fight-or-flight” responses to stressors (within seconds) through its two divisions: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). During stress, sympathetic neurons in the spinal cord release acetylcholine (ACh), which activates acetylcholine receptors on chromaffin cells in the head kidney of fish. This triggers depolarization and Ca2+ influx, facilitating the release of catecholamines (CAs) into the bloodstream and subsequent action on peripheral target tissues [160,161]. In the PNS, efferent parasympathetic nerve signals are transmitted from the central nervous system to their targets via preganglionic and postganglionic neurons. ACh serves as a major neurotransmitter in the PNS and is activated when the stressful state is alleviated [162]. Generally, the two systems regulate important functions in an antagonistic manner to achieve homeostasis during stress [161].
Glutamate has been found to activate NMDA/AMPA receptors in brain regions such as the paraventricular nucleus (PVN), increasing sympathetic outflow [163]. Conversely, the activation of metabotropic mGluRs in the PVN effectively reduces sympathetic outflow [164]. Additionally, GABAergic inhibition in the PVN can suppress sympathetic activation through GABAA and GABAB receptors [165]. Studies have demonstrated that chromaffin cells express various iGluRs and mGluRs, which exert distinct effects on the regulation of basal and glutamate-induced CA secretion via the nitric oxide/3′,5′-cyclic guanosine monophosphate (NO/cGMP) pathway. Furthermore, the glutamate-mediated activation of neuronal nitric oxide synthase (nNOS) in chromaffin cells highlights the involvement of both PKA and PKC signaling pathways in the apoptotic effects induced by glutamate [166]. In chromaffin cells, GABA is synthesized, stored in granules, and released upon nicotinic ACh receptor activation. Exogenous GABA stimulates GABAA receptors, inducing CA secretion via action potentials while inhibiting trans-synaptically evoked excitation [109]. GABA facilitates secretion when synaptic excitation is low, but inhibits it when excitation is high [167]. Although chromaffin cells do not synthesize serotonin (5-HT), they accumulate small amounts through serotonin transporter (SERT)-mediated uptake [168]. Recent studies have demonstrated that 5-HT1A receptors inhibit catecholamine (CA) secretion and exocytosis from adrenal chromaffin cells via an atypical mechanism that does not involve modulation of cellular excitability, voltage-gated Ca2+ channels, potassium channels, or intracellular calcium levels [169].
The BSC axis can rapidly increase blood pressure and heart rate during acute stress and quickly subside after stress due to reflex parasympathetic activation [170]. However, chronic stress continuously activates the SNS, leading to increased synthesis, storage, and basal levels of CAs, as well as decreased levels of ACh [162]. In fish, it has been recognized that both acute and chronic stressors, such as air exposure [171], handling stress [153], and hypoosmotic shock [172], can induce CA biosynthesis and elevate plasma CA concentrations. In coral trout, acute stress can trigger rapid changes in body color through the activation of catecholaminergic signaling. In vitro incubation with NE induces the aggregation of chromatosomes, while intraperitoneal injection leads to the lightening of body color [173]. In gilthead sea bream, elevated plasma CAs were observed under conditions of chronic high stocking density and food deprivation, suggesting activation of the BSC axis during chronic stress [135].

3.2.2. Hypothalamus–Pituitary–Interrenal (HPI) Axis

In the HPI axis, stress activates hypophysiotropic neurons in the PVN of the hypothalamus to secrete arginine vasotocin (AVT) and corticotropin-releasing hormone (CRH). These releasing hormones stimulate the anterior pituitary to produce pro-opiomelanocortin (POMC), which is subsequently processed into adrenocorticotropic hormone (ACTH), also known as corticotropin, and released into the bloodstream. Upon reaching the head kidney, ACTH binds to melanocortin 2 receptor (MC2R) on cortisol-producing cells, activating steroidogenic acute regulatory protein (STAR) for the generation of corticosteroids, a class of steroid hormones [174]. Cortisol, the primary corticosteroid in fish, primarily functions to increase blood flow and heart rate and mobilize energy stores to muscles during stress by binding to corticosteroid receptors, namely the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR), on target cells [175]. As the end-product of HPI axis activation, cortisol also induces negative feedback on the HPI axis, regulating the synthesis and secretion of hypothalamic CRH and pituitary ACTH.
In fish, various stressors, such as temperature [176], crowding [177], hypoxia [178], light–dark cycles, and fasting [179], have been shown to activate the HPI axis, with cortisol levels widely recognized as indicators of the stress response. In rainbow trout and lake whitefish, the cortisol response to stressors is absent immediately after hatching when siblings experience stress during the embryonic stage [178,180]. The activation of the HPI axis typically occurs in response to acute and high-intensity stress, depending on both intensity and duration. Conversely, under chronic stress conditions, the capacity of the HPI axis to mount an appropriate stress response diminishes, particularly within the pituitary gland [181]. Notably, chronic heavy metal exposure has been found to alter the HPI axis and inhibit cortisol responses to acute stressors [182,183]. However, in Atlantic salmon (Salmo salar), chronic stress was observed to prolong HPI axis activation over eight weeks of daily crowding [177]. Additionally, maternal conditions influence the HPI axis response to stress. For example, maternal cortisol exposure or sequestration during embryogenesis mediates the development and sensitivity of the HPI axis in offspring [184,185].
Moreover, the neural and neuroendocrine systems exhibit largely complementary actions during stress. For instance, noradrenergic and adrenergic projections to the hypophysiotrophic zone of the PVN participate in HPI activation [186]. ACh stimulates cortisol secretion through mAChRs on adrenal cells [187,188]. Meanwhile, cortisol has been reported to induce ACh accumulation, resulting in tissue damage and impairing regeneration [189]. CRH-releasing neurons project to the locus coeruleus, which directly sends projections to sympathetic and parasympathetic preganglionic neurons to enhance sympathetic activity and reduce parasympathetic activity [162].
Strong evidence indicates that glutamate drives hypothalamic–pituitary–adrenal (HPA) axis stress responses through excitatory signaling mediated by iGluRs activity [190]. Other studies have shown that glutamate participates in the feedback loop of the HPA axis via kainate receptors and mGluRs, which inhibit HPA activation [191]. Additionally, cortisol secretion during acute stress induces glutamate release in limbic and cortical regions [192], while inhibition of glutamate receptors stimulates ACTH release during stress [193]. Taken together, these findings suggest that glutamate plays a complex role in exciting CRH neurons, acting at multiple levels to drive HPA axis responses and limit over-activation. The role of GABA in the HPA axis is well established. CRH neurons are regulated by both phasic and tonic GABAergic inhibition, distinct types of GABAergic inhibition mediated by specific subtypes of GABAA receptors [194]. Cortisol also increases GABAergic signaling through changes in the expression of postsynaptic GABAA receptors and tonic GABAergic inhibition, contributing to the inhibition of CRH neurons [195]. These results provide novel negative feedback for the HPA axis.
NE and E are known to stimulate hypothalamic CRH secretion via alpha-1 and alpha-2 receptors, while CAs may also contribute to the feedback loop of the HPA axis. Studies investigating corticosterone’s long-term regulation of Crh and Avp gene expression in the paraventricular hypothalamus (PVH) using a saporin-based immunocytotoxin targeting catecholaminergic neurons revealed that corticosterone’s suppression of Crh expression requires intact catecholaminergic innervation. Similarly, elevated Avp expression post-adrenalectomy was suppressed in lesioned animals. These findings demonstrate that corticosterone–catecholamine interactions critically modulate hypothalamic Crh and Avp expression [196]. Additionally, dopamine (DA) regulates HPI axis activation during stress by interacting with its receptors on CRH-containing neurons in the PVN [197]. Dopaminergic neurons, the primary source of DA, also seem to regulate the HPA axis [198]. Several dopaminergic brain regions express glucocorticoid receptors, and administration of glucocorticoids increases extracellular DA levels [198].
Studies have shown that midbrain serotonin neurons directly innervate CRH cells in the hypothalamic PVN to stimulate CRH and POMC release, leading to ACTH secretion and activation of the HPA axis. This process is mediated by 5-HT1A, 5-HT2A, 5-HT2C, and possibly also 5-HT1B receptors [199,200]. In human colonic enterochromaffin (EC) cells, EC cell-specific CRH1 expression and their activation pathways driving serotonin release/synthesis have been identified [201]. Chronic corticosterone exposure elevates tryptophan hydroxylase 2 (TPH2) protein expression and mediates hypersensitivity of stress/anxiety circuits via opposing CRH receptor actions on serotonin synthesis [202].

3.2.3. Caudal Neurosecretory System (CNSS)

In addition to the common neuroendocrine systems, fish possess a distinct neuroendocrine system located at the caudal end of the spinal cord, referred to as the CNSS. This system comprises a neurohemal organ known as the urophysis and magnocellular peptide-synthesizing neuroendocrine neurons, termed Dahlgren cells, which were first described in 1914 [203]. CNSS plays the important roles in osmoregulation [204], thermoregulation [205], and other stress responses, including ammonia toxicity, hypoxia, isolation, and subordination [206]. Studies have shown that the activities of the CNSS are innervated by the midbrain and medulla [207], followed by the release of neuropeptides into the circulation via the tail vein. Recent studies have demonstrated that several neurotransmitters, including DA [208], adrenaline [209], serotonin [210], taurine [211], nitric oxide [204], Glu [212] and GABA [213], regulate the firing activities of Dahlgren cells through their respective receptors in the CNSS, reflecting the crosstalk between the nervous system and the CNSS. The major neuropeptides synthesized in the CNSS include arginine AVT, isotocin (IT) [214], CRH, Urotensin I (UI, uts1) [215] and Urotensin II (UII, uts2) [216], parathyroid hormone related protein (PTHrP) [217]. It has been established that the CNSS is the primary circulating source of CRH, UI, UII, and PTHrP in fish [217,218,219].
Research has demonstrated that various stressors, such as handling, osmotic pressure changes, thermal conditions, hyperammonemia, hypoxia, isolation, and subordination, influence the expression of crh, uts1, and uts2 synthesized in the CNSS [204,206,220,221,222]. The expression changes of these genes in the CNSS vary depending on the type of stressor: handling stress increases the expression of all three genes; acute seawater/freshwater transfer experiments elevate the expression of uts1 while decreasing that of uts2; acute hypothermal stress, but not hyperthermal stress, enhances the expression of all three genes; subordination has no significant effect; isolation reduces the expression of crh and uts1, whereas hyperammonemia and hypoxia increase the expression levels of crh and/or uts1. Furthermore, both in vivo and in vitro studies have shown that administration of UI and UII increases cortisol secretion [223]. Compared with individual administration of ACTH, UI, or UII, the enhanced release of cortisol following perifusion with a combination of ACTH and either UI or UII is significantly greater, indicating that interrenal UI and UII potentiate the steroidogenic effects of ACTH [224]. Given that fish exhibit relatively low blood pressure and slow fluid circulation velocity, the CNSS may contribute to stress responses by providing complementary regulation through the control of circulating levels of stress-related hormones and modulating cortisol production in response to specific stressors. Current studies suggest that the contributions of the brain and CNSS to stress responses depend on factors such as the type of stressor, duration, intensity, and specific regions within fish [225].

4. Dietary Supplements on Stress Mitigation Through Neuroendocrine and Neurotransmitter Regulations

Traditional pharmaceutical therapies in aquaculture typically focus on addressing waterborne substances that induce infections following disease onset. These treatments are often palliative and may lead to secondary environmental pollution, such as the use of antibiotics and malachite green for treating bacterial and fungal infections. However, most infections occur as a result of failed stress regulation mechanisms. The use of dietary supplements to enhance beneficial effects and mitigate harmful effects of stress represents a more environmentally friendly approach. This strategy appears to be a viable and sustainable solution for developing stress mitigation measures, improving immunocompetence, and enhancing disease resistance in aquatic animals. Based on their components, these supplements can be categorized into nutritional and non-nutritional types.

4.1. Nutritional Supplements

Recently, dietary intervention with amino acids, such as phenylalanine (Phe), has been considered a promising approach to reduce stress-induced physiological injury in fish through neuroendocrine and neurotransmitter regulation [226].
Phe and tyrosine (Tyr) serve as precursors for the biosynthesis of catecholamine neurotransmitters, including NE, E, and DA [227,228,229]. The oral administration of Phe-enriched diets has been found to elevate DA levels and minimize the effects of repeated handling stress in juvenile soles (Solea senegalensis) [230]. Dietary supplementation with 5% Phe has been shown to reduce several stress markers (glucose, cortisol, NE, E, and DA) in meagres (Argyrosomus regius) during netting/chasing stress but not in gilthead seabreams (Sparus aurata) [229]. However, gilthead seabreams fed diets supplemented with 5% Phe or Tyr exhibited reduced levels of various stress markers (including glucose, lactate, proteins, and cortisol) during chronic confinement and netting/chasing stress [231] In fact, increasing Phe concentration in the diet reduces plasma catecholamine hormone levels. This occurs because elevating the blood concentration of this amino acid enhances its passage through the blood-brain barrier relative to other amino acids, including tyrosine, thereby inhibiting catecholamine synthesis [229]. Furthermore, Phe supplementation has been found to eliminate reactive oxygen species (ROS) and mitigate oxidative damage during stress [231,232]. Additionally, dietary Phe at levels ranging from 0.88% to 2.13% has been demonstrated to significantly enhance growth performance, digestive efficiency, absorption capacity, antioxidant activity, and intestinal health in both rainbow trout and tilapia [233,234].
Tryptophan (Trp) is an essential amino acid that plays a critical role in regulating the stress response. It serves as a precursor for serotonin and melatonin synthesis. Studies have demonstrated that dietary Trp supplementation at a level of 0.72% can reduce serum cortisol levels and oxidative stress responses during thermal stress in rohu (Labeo rohita) [235]. Additionally, dietary Trp at 5 g·kg−1 has been shown to enhance intestinal antioxidant capacity and modulate inflammatory responses under high-stocking density conditions in rainbow trout [236]. Tryptophan supplementation has also been associated with decreased levels of POMC-like peptides, which are involved in ACTH and cortisol secretion. When stressed European seabass (Dicentrarchus labrax) fed a Trp-supplemented diet were subjected to an inflammatory stimulus, plasma cortisol levels decreased, and the expression of genes involved in the neuroendocrine response was altered, seemingly mediated by changes in serotonergic activity [237]. Dietary Trp at levels ranging from 3.81 to 3.89 g·kg−1 has been shown to improve fish growth, antioxidant capacity, and intestinal innate immunity in grass carp [238]. Meanwhile, a study investigating the effects of a Trp-deficient diet in juvenile European seabass revealed increased plasma cortisol levels and compromised immune cell responses, reflecting a decline in disease resistance [239]. However, it remains unclear whether stress mitigation is caused by the amino acids themselves or their metabolites. Studies have demonstrated that the antioxidant potential of tryptophan is primarily attributed to its metabolites, such as melatonin, 5-hydroxytryptophan, indole-3-acetic acid, 3-hydroxyanthranilic acid, and 3-hydroxykynurenine [240].
In addition to amino acids, certain fatty acids and vitamins have also been found to regulate cortisol release during stress. For instance, prostaglandin E2 (PGE2) has been reported to modulate the hypothalamus–pituitary–interrenal (HPI) axis and affect cortisol release in fish [241]. Vitamins are increasingly being used to mitigate various husbandry and physical stressors in aquaculture. For example, dietary administration of vitamins C and E protects fish from death or other negative effects induced by stressors such as heat, hypoxia, and handling [242,243,244]. More importantly, vitamins C and E appear to mitigate stress by modulating neuroendocrine and immune reactions. High doses of vitamins C and E block steroidogenesis by preventing the conversion of unsaturated lipids into cholesterol esters and hindering cortisol formation [244,245,246]. However, vitamin C and E supplementation does not seem to influence growth in rainbow trout [247].

4.2. Non-Nutritional Supplements

In addition to nutritional additives, certain non-nutritional compounds are also known to modulate immune function and enhance stress tolerance in fish. Levamisole, a synthetic phenyl imidazothiazole compound, has been reported to improve stress tolerance [246,248]. Even with low supplementation of levamisole (0.1%), rainbow trout fingerlings exhibit enhanced tolerance during crowded stress conditions [249]. After 15 days of oral administration, levamisole has been found to modulate plasma cortisol levels and enhance innate immune responses against bacterial infections in air-exposure-stressed pacu (Piaractus mesopotamicus) [250]. Clinical studies in humans have shown that levamisole can reduce or inhibit steroid production and affect glucocorticosteroid levels [251]. Another in vitro experiment demonstrated that levamisole significantly suppresses the elevation of ROS induced by glutamate through stabilizing mitochondrial membrane potential, thereby protecting cells from death [252]. However, the mechanism of action of levamisole in fish remains poorly understood.
Recently, the application of biological derivatives, such as prebiotics and probiotics, has been shown to mitigate stress by increasing neurotransmitter levels in the brain and modifying the host–microbial community in the fish intestine [253,254]. The use of mixed water probiotics has been reported to reduce cortisol levels and improve tolerance to various husbandry-related stressors in fish [255,256].
Furthermore, certain herbal medicines have also been reported to exhibit anti-stress effects in aquatic animals. Emodin, an active component of anthraquinone extracts, protects Wuchang bream (Megalobrama amblycephala) from crowding stress by reducing serum cortisol levels [244], a finding also confirmed in common carp [257]. By targeting the NF-κB signaling pathway, emodin enhances antioxidant capacity [258]. In vitro experiments have shown that emodin induces antioxidant defenses in peripheral blood leukocytes via the Nrf2-Keap1 signaling pathway [259]. Moreover, dietary supplementation with 1% turmeric significantly reduces plasma cortisol levels and enhances lysozyme activity during transportation, making it an effective feed additive for mitigating the adverse effects of transportation stress in common carp [260].

5. Conclusions and Perspectives

This review systematically summarizes the neuroendocrine and neurotransmitter responses, as well as the complex inter-system communication networks in fish when exposed to common stressors in aquaculture production. Furthermore, dietary interventions for stress mitigation with practical relevance are discussed. Specifically, phenylalanine, tyrosine, and tryptophan serve as precursors of neurotransmitters to alleviate stress by modulating the BSC and HPI axes. Meanwhile, probiotics and herbal compounds help maintain neurotransmitter balance and mitigate oxidative damage. Future research on fish neural and neuroendocrine stress responses should prioritize the following areas: (1) fundamental investigations into fish stress responses, encompassing multi-stressor interactions, species-specific neuroendocrine reactions, and neural-endocrine crosstalk mechanisms; and (2) the exploration of highly efficient and cost-effective aquafeed formulations, along with a deeper understanding of their mechanisms of action in stress mitigation, to advance sustainable stress management strategies in intensive aquaculture.

Author Contributions

M.Y.: Conceptualization, Software, Investigation, Resources, Visualization, Writing—original draft, Writing—review and editing. Q.F.: Investigation, Writing—original draft. W.L.: Conceptualization, Supervision. X.W.: Supervision. T.H.: Conceptualization. C.-M.C.: Conceptualization, Funding acquisition, Supervision, Writing—original draft. S.C.: Supervision, Writing—review and editing, Funding acquisition. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by Ningbo Natural Science Foundation (Youth Foundation, 2024J449), the 2024 Yongjiang Talent Introduction Programme (2024A-373-G), the Public Welfare Research Project of Ningbo (2024S087), Research Start-up Funding Project at Ningbo University (ZX2024000042 and ZX2024000043), the Science and Technology Development Fund, Macau S.A.R (FDCT) (File no. 0073/2023/RIA2 and 005/2023/SKL), and the Research Fund of University of Macau (File no. MYRG-GRG2023-00048-ICMS).

Data Availability Statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest.

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Figure 1. Graphical description of the synthesis and deliver of neurotransmitters during stress in fish. Cholinergic system: acetyl-CoA and choline synthesize acetylcholine (ACH) under the catalysis of choline acetyltransferase (CHAT). ACH is stored in vesicles, released into the synaptic cleft to function, and then decomposed into choline and acetic acid by acetylcholinesterase (ACHE). Choline can re-enter the synthesis process. Dopaminergic system: tyrosine undergoes enzymatic reactions to produce dopamine (DA), norepinephrine (NE), and epinephrine (E), which are involved in neural signal transduction. Glutamatergic system: glutamine is converted into glutamate (Glu) by glutaminase. Glu can be used to synthesize γ-aminobutyric acid (GABA). Both Glu and GABA are stored in vesicles and released to function. Serotonergic system: tryptophan is converted into serotonin (5-HT) under the action of tryptophan hydroxylase and other enzymes. 5-HT can be recycled by the serotonin transporter (SERT).
Figure 1. Graphical description of the synthesis and deliver of neurotransmitters during stress in fish. Cholinergic system: acetyl-CoA and choline synthesize acetylcholine (ACH) under the catalysis of choline acetyltransferase (CHAT). ACH is stored in vesicles, released into the synaptic cleft to function, and then decomposed into choline and acetic acid by acetylcholinesterase (ACHE). Choline can re-enter the synthesis process. Dopaminergic system: tyrosine undergoes enzymatic reactions to produce dopamine (DA), norepinephrine (NE), and epinephrine (E), which are involved in neural signal transduction. Glutamatergic system: glutamine is converted into glutamate (Glu) by glutaminase. Glu can be used to synthesize γ-aminobutyric acid (GABA). Both Glu and GABA are stored in vesicles and released to function. Serotonergic system: tryptophan is converted into serotonin (5-HT) under the action of tryptophan hydroxylase and other enzymes. 5-HT can be recycled by the serotonin transporter (SERT).
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Figure 2. The schematic diagram shows the neuroendocrine systems in fish. When stress signal is perceived, the neurotransmitter acetylcholine (ACh) will be released from sympathetic nerve fibers to (i) stimulate the catecholamine (CA) synthesis in the chromaffin cells; (ii) participate in activating the hypothalamus releasing corticotropin-releasing hormone (CRH) and stimulate the pituitary gland releasing adrenocoticotropic hormone (ACTH), which can induce cortisol secretion in the interrenal cells. (iii) The stress signal will also activate the neurons in midbrain regulating the caudal neurosecretory system (CNSS). CRH, urotensin I (UI), and urotensin II (UII) are synthesized in the Dahlgren cells, stored in the urophysis and released into the circulation from tail vein.
Figure 2. The schematic diagram shows the neuroendocrine systems in fish. When stress signal is perceived, the neurotransmitter acetylcholine (ACh) will be released from sympathetic nerve fibers to (i) stimulate the catecholamine (CA) synthesis in the chromaffin cells; (ii) participate in activating the hypothalamus releasing corticotropin-releasing hormone (CRH) and stimulate the pituitary gland releasing adrenocoticotropic hormone (ACTH), which can induce cortisol secretion in the interrenal cells. (iii) The stress signal will also activate the neurons in midbrain regulating the caudal neurosecretory system (CNSS). CRH, urotensin I (UI), and urotensin II (UII) are synthesized in the Dahlgren cells, stored in the urophysis and released into the circulation from tail vein.
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Table 1. Common stressors in aquaculture.
Table 1. Common stressors in aquaculture.
Type of StressorExampleReferences
PhysicalWater temperature;[15,16,17]
Photoperiod;[18,19,20]
Sound;[21,22,23]
Turbidity[24,25,26]
…
ChemicalpH; [27,28,29]
Salinity;[30,31,32,33]
Dissolved oxygen; [34,35,36]
Alkalinity;[37,38]
Carbon dioxide complexities;[39,40,41]
Nitrite;[42,43,44]
Ammonia; [45,46,47]
Hydrogen sulfide; [48,49]
Iron; [50,51]
Heavy metal;[52,53,54]
Pesticides[55,56,57]
…
BiologicalAlgal toxicosis;[58,59]
Microorganisms;[60,61,62]
Parasites;[63,64,65]
Predators;[66,67,68]
Social rank;[69,70,71]
Environmental enrichment[72,73,74]
…
ProceduralOvercrowding;[75,76,77]
Handling;[78,79,80]
Netting[81,82]
Feeding;[83,84,85]
Transportation[86,87,88]
…
Table 2. Comparison of neuroendocrine systems in fish.
Table 2. Comparison of neuroendocrine systems in fish.
SystemPrimary ComponentResponse TimingMagnitude/Duration
Brain–Sympathetic–Chromaffin Cell (BSC) AxisBrain (sympathetic neurons);
Sympathetic nerves;
Chromaffin cells (in head kidney; catecholamines)		Immediate (<1 min to hours)Rapid onset;
Short duration (minutes to hours);
High peak magnitude
Hypothalamus–Pituitary–Interrenal (HPI) AxisHypothalamus (CRH/ACTH-releasing factors);
Pituitary (ACTH);
Interrenal tissue (cortisol/corticosterone)		Delayed (hours to days)Slower onset;
Long-lasting (days to weeks);
Moderate-to-high magnitude (sustained)
Caudal Neurosecretory System (CNSS)Dahlgren cell (urotensins, isotocin, CRH);
Urophysis;		Variable (minutes to hours, depending on stimulus)Moderate onset;
Moderate duration (hours);
Target-specific magnitude
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Yuan, M.; Fang, Q.; Lu, W.; Wang, X.; Hao, T.; Chong, C.-M.; Chen, S. Stress in Fish: Neuroendocrine and Neurotransmitter Responses. Fishes 2025, 10, 307. https://doi.org/10.3390/fishes10070307

AMA Style

Yuan M, Fang Q, Lu W, Wang X, Hao T, Chong C-M, Chen S. Stress in Fish: Neuroendocrine and Neurotransmitter Responses. Fishes. 2025; 10(7):307. https://doi.org/10.3390/fishes10070307

Chicago/Turabian Style

Yuan, Mingzhe, Qian Fang, Weiqun Lu, Xubo Wang, Tianwei Hao, Cheong-Meng Chong, and Shan Chen. 2025. "Stress in Fish: Neuroendocrine and Neurotransmitter Responses" Fishes 10, no. 7: 307. https://doi.org/10.3390/fishes10070307

APA Style

Yuan, M., Fang, Q., Lu, W., Wang, X., Hao, T., Chong, C.-M., & Chen, S. (2025). Stress in Fish: Neuroendocrine and Neurotransmitter Responses. Fishes, 10(7), 307. https://doi.org/10.3390/fishes10070307

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