The roles of co-transmission in neural network modulation

doi:10.1016/S0166-2236(00)01723-9

Trends in Neurosciences

Volume 24, Issue 3, 1 March 2001, Pages 146-154

https://doi.org/10.1016/S0166-2236(00)01723-9 Get rights and content

Abstract

Neuromodulation provides considerable flexibility to the output of neural networks. In spite of the extensive literature documenting the presence of modulatory peptide co-transmitters in many neurons, considerably less is known about the specific roles of co-transmission in circuit function. This review describes some of the potential consequences of peptide co-transmission in functional circuits, using specific examples from recent work on the actions of identified peptidergic projection neurons acting on the multifunctional neural network within the crustacean stomatogastric ganglion. This system reveals that co-transmission provides projection neurons with a rich assortment of strategies for eliciting multiple outputs from a multifunctional network.

Section snippets

Proctolin distribution and actions

Proctolin is a pentapeptide (RYLPT) found in arthropods ⁴¹. The neuropil of the STG is densely proctolin-immunoreactive, but there is no proctolin immunoreactivity in STG somata ⁴². Only three pairs of proctolin-staining neurons innervate the STG (⁴³). These include the modulatory proctolin neurons (MPNs) that have somata in the oesophageal ganglion (OG) (44, 45), and modulatory commissural neuron 1 (MCN1) (⁴⁶) and modulatory commissural neuron 7 (MCN7) (⁴⁶) that have somata in the commissural

Many neurotransmitters converge onto the same current

Many of the neuromodulators that influence the pyloric circuit share the ability to excite and modify the pyloric rhythm 29, 30. However, when they are individually bath applied, each modulator elicits a different version of this rhythm. This result suggested that each modulator might act on a different set of currents expressed in a different subset of the pyloric neurons. Indeed, this appears to be the case for the actions of serotonin and dopamine 33, 34, 37, 38, 54.

By contrast, at least

Patterns of co-localization in identified projection neurons

Most of what we know about modulation of circuit activity in all nervous systems derives from studies using exogenously applied neuromodulators 3, 59, 60, 61, 62. This is a consequence of the experimental convenience of this approach, and the technical difficulties associated with studying the actions of individual modulatory neurons with identified transmitters. However, there are several reasons why neuronal modulation of circuit activity might differ significantly compared with that

Three proctolin-containing neurons elicit different STG motor patterns

The three proctolin-containing projection neurons elicit different STG motor patterns 46, 66. Intracellular stimulation of either MPN, MCN1 or MCN7 influences the pyloric rhythm, but each neuron modifies this rhythm differently (Fig. 4). Specifically, MPN and MCN1 both increase the speed of slowly cycling pyloric rhythms, but elicit different patterns of pyloric activity and different activity levels in pyloric neurons. By contrast, comparable stimulation of MCN7 slows down the pyloric rhythm

Segregation of co-transmitter actions

As described earlier, the presence of co-transmitters allows added flexibility because different co-transmitters can influence separate target neurons (Fig. 1c,d). There are, as yet, only a few such cases documented, including the actions of the multi-peptide neuroendocrine bag cells in Aplysia ²⁶, the cholinergic and peptidergic neurons innervating the frog sympathetic ganglion ⁷, and the actions of the GPR sensory neurons in the crab STG (69, 70, 71). The co-transmitters released from MCN1

Convergence and divergence of network targets in co-transmitter release

It is not necessary for a neuron to arborize in spatially separate regions of the nervous system in order for its co-transmitters to influence different target neurons 7, 26, 69, 70, 71. How such a local separation of target neurons contributes to circuit modulation by modulatory neurons is being elucidated by the actions of MCN1 in the STG. The MCN1 peptide co-transmitters (proctolin and CabTRP Ia) have both convergent and divergent actions on pyloric and gastric mill neurons. Convergence is

The role of convergence in state-dependent modulator action

The actions of proctolin and other neuromodulators on the pyloric rhythm are state-dependent. For example, both proctolin and CabTRP Ia are much more-strongly excitatory when the preparation is relatively inactive, and evoke less-strong actions when applied to preparations with strong pyloric rhythms. Swensen and Marder ⁵² showed that saturating concentrations of proctolin and CabTRP Ia occlude each others actions. This means that, when one of the peptides has already strongly activated

Do distinct co-transmitter complements ensure distinct actions on the same circuit?

The fact that MPN and MCN1 both contain proctolin and GABA, but only MCN1 contains CabTRP Ia, suggested that their distinct actions in the STG resulted from the presence of CabTRP 1a in MCN1. This hypothesis was tested by blocking the actions of CabTRP Ia with Spantide I, a broad-spectrum tachykinin-receptor blocker ⁶⁶. In the pres ence of Spantide I, MCN1 stimulation no longer elicits a gastric mill rhythm, making its actions more like those of MPN. The MPN- and MCN1-elicited pyloric rhythms

Concluding remarks

The study of the neuromodulatory actions of amines and peptides shows that networks are not hard-wired, but are reconfigured by the modulatory environment. More-recent studies of the actions of identified projection neurons containing proctolin indicate that the co-transmitter complement plays important roles in enabling the disparate actions of these neurons, in spite of a remarkable degree of convergence of neuromodulator action. These convergent actions might partially account for

Acknowledgements

We thank all past and present members of the Marder and Nusbaum laboratories who have participated in these studies. This work was supported by grants from the National Institutes of Health, National Science Foundation and the W.M. Keck Foundation.

References (77)

I. Kupfermann
Functional studies of cotransmission
Physiol. Rev.
(1991)
K.R. Weiss
Peptidergic co-transmission in Aplysia: functional implications for rhythmic behaviors
Experientia
(1992)
M. Verhage
Differential release of amino acids, neuropeptides and catecholamines from isolated nerve terminals
Neuron
(1991)
K.A. Sigvardt
The bag cells of Aplysia as a multitransmitter system: identification of alpha bag cell peptide as a second neurotransmitter
J. Neurosci.
(1986)
A. Ayali et al.
Monoamine control of the pacemaker kernel and cycle frequency in the lobster pyloric network
J. Neurosci.
(1999)
A.N. Starratt et al.
Structure of the pentapeptide proctolin, a proposed neurotransmitter in insects
Life Sci.
(1975)
E. Marder
Modulatory action and distribution of the neuropeptide proctolin in the crustacean stomatogastric nervous system
J. Comp. Neurol.
(1986)
M.L. Mayer
Voltage-dependent block by Mg²⁺ of NMDA responses in spinal cord neurones
Nature
(1984)
D. Parker
Co-localized neuropeptide Y and GABA have complementary presynaptic effects on sensory synaptic transmission
Eur. J. Neurosci.
(1998)
R.M. Harris-Warrick et al.
Modulation of neural networks for behavior
Annu. Rev. Neurosci.
(1991)

Y-Y. Peng et al.

Continuous repetitive stimuli are more effective than bursts for evoking LHRH release in bullfrog sympathetic ganglia

J. Neurosci.

(1991)

M. Cazalis

The role of patterned burst and interburst interval on the excitation-coupling mechanism in the isolated rat neural lobe

J. Physiol.

(1985)

E. Marder et al.

Neurotransmitter modulation of the stomatogastric ganglion of decapod crustaceans

E. Marder et al.

Modulatory control of multiple task processing in the stomatogastric nervous system

R.E. Flamm et al.

Aminergic modulation in lobster stomatogastric ganglion. I. Effects on motor pattern and activity of neurons within the pyloric circuit

J. Neurophysiol.

(1986)

R.E. Flamm et al.

Aminergic modulation in lobster stomatogastric ganglion. II. Target neurons of dopamine, octopamine, and serotonin within the pyloric circuit

J. Neurophysiol

(1986)

R.M. Harris-Warrick

Dopamine modulation of transient potassium current evokes phase shifts in a central pattern generator network

J. Neurosci.

(1995)

Cited by (278)

Role of the locus coeruleus and basal forebrain in arousal and attention
2022, Brain Research Bulletin
Citation Excerpt :
As more targeted tools became available to exclusively manipulate other populations of BF neurons, it became clear that BF-PV neurons also play an important role in attentional processing (Burk and Sarter, 2001; Kim et al., 2015, McNally et al., 2021). Co-release of more than one chemical messenger enhances neural network flexibility, for example, by expanding the range of temporal and spatial representation (Nusbaum, 2001). When comparing the influence of BF-PV neurons to that of LC-NE and BF-ACh-mediated neuromodulation, the former is capable of far more rapid, but transient, effects that occur on the scale of milliseconds rather than seconds (Shine, 2019).
Experimental evidence has implicated multiple neurotransmitter systems in either the direct or indirect modulation of cortical arousal and attention circuitry. In this review, we selectively focus on three such systems: 1) norepinephrine (NE)-containing neurons of the locus coeruleus (LC), 2) acetylcholine (ACh)-containing neurons of the basal forebrain (BF), and 3) parvalbumin (PV)-containing gamma-aminobutyric acid neurons of the BF. Whereas BF-PV neurons serve as a rapid and transient arousal system, LC-NE and BF-ACh neuromodulation are typically activated on slower but longer-lasting timescales. Recent findings suggest that the BF-PV system serves to rapidly respond to even subtle sensory stimuli with a microarousal. We posit that salient sensory stimuli, such as those that are threatening or predict the need for a response, will quickly activate the BF-PV system and subsequently activate both the BF-ACh and LC-NE systems if the circumstances require longer periods of arousal and vigilance. We suggest that NE and ACh have overlapping psychological functions with the main difference being the precise internal/environmental sensory situations/contexts that recruit each neurotransmitter system – a goal for future research to determine. Implications of dysfunction of each of these three attentional systems for our understanding of neuropsychiatric conditions are considered. Finally, the contemporary availability of research tools to selectively manipulate and measure the activity of these distinctive neuronal populations promises to answer longstanding questions, such as how various arousal systems influence downstream decision-making and motor responding.
Emerging role of astrocytes in oxytocin-mediated control of neural circuits and brain functions
2022, Progress in Neurobiology
The neuropeptide oxytocin has been in the focus of scientists for decades due to its profound and pleiotropic effects on physiology, activity of neuronal circuits and behaviors, among which sociality. Until recently, it was believed that oxytocinergic action exclusively occurs through direct activation of neuronal oxytocin receptors. However, several studies demonstrated the existence and functional relevance of astroglial oxytocin receptors in various brain regions in the mouse and rat brain. Astrocytic signaling and activity is critical for many important physiological processes including metabolism, neurotransmitter clearance from the synaptic cleft and integrated brain functions. While it can be speculated that oxytocinergic action on astrocytes predominantly facilitates neuromodulation via the release of specific gliotransmitters, the precise role of astrocytic oxytocin receptors remains elusive. In this review, we discuss the latest studies on the interaction between the oxytocinergic system and astrocytes, including detailed information about intracellular cascades, and speculate about future research directions on astrocytic oxytocin signaling.
The emergence and influence of internal states
2022, Neuron
Animal behavior is shaped by a variety of “internal states”—partially hidden variables that profoundly shape perception, cognition, and action. The neural basis of internal states, such as fear, arousal, hunger, motivation, aggression, and many others, is a prominent focus of research efforts across animal phyla. Internal states can be inferred from changes in behavior, physiology, and neural dynamics and are characterized by properties such as pleiotropy, persistence, scalability, generalizability, and valence. To date, it remains unclear how internal states and their properties are generated by nervous systems. Here, we review recent progress, which has been driven by advances in behavioral quantification, cellular manipulations, and neural population recordings. We synthesize research implicating defined subsets of state-inducing cell types, widespread changes in neural activity, and neuromodulation in the formation and updating of internal states. In addition to highlighting the significance of these findings, our review advocates for new approaches to clarify the underpinnings of internal brain states across the animal kingdom.
Dopaminergic muhsroom body neurons in Drosophila: Flexibility of neuron identity in a model organism?
2022, Neuroscience and Biobehavioral Reviews
In classical neuroscience, Dale´s principle postulates that neuronal identity is conferred by the specific neurotransmitter that it releases. However, the brain might be more tractable to specific situations regardless of specific specialisation which may contradict this principle. Hence, this constrained approach of how we perceive and study the nervous system must be revisited and revised, specifically by studying the dopaminergic system. We presume a relatively flexible change in the dopaminergic system due to neuronal activity or environmental changes. While the parallel between the reward system of mammals and insects is generally well accepted, herein, we extend the idea that the insect nervous system might also possess incredible plasticity, similar to the mammalian system. In this review, we critically evaluate the available information about the reward system in vertebrates and invertebrates, emphasising the dopaminergic neuronal plasticity, a challenge to the classical Dale’s principle. Thus, neurotransmitter switching significantly disrupts the static idea of neural network organisation and suggests greater possibilities for a dynamic response to the current life context of organisms.
A low-dimensional hybrid p-i-n heterojunction neuromorphic transistor with ultra-high UV sensitivity and immediate switchable plasticity
2021, Applied Materials Today
Citation Excerpt :
Such stable memory states for detecting external information provides the possibility of future electronic information identify. Different combinations of neurotransmitters could be released from a subset of synaptic boutons in an individual neuron to convey different information [38,39]. A switchable plasticity between long-term and short-term can be emulated by altering neuromodulators [40–42].
We demonstrate a photoelectric neuromorphic transistor (PENT), consisting of a hybrid p-i-n heterojunction channel of vertically phase-separated 2,7-dioctyl[1]benzothieno[3,2-b][1]benzothiophene (C8-BTBT) /poly(methyl methacrylate) (PMMA) as a two-dimensional (2D) sheath and highly-aligned array of long continuous zinc oxide (ZnO) nanowires (NWs) as a quasi-one dimensional (Q1D) core. This is the first report of a hybrid p-i-n heterojunction being developed on a NW-based PENT. The device integrates both optical sensing and electrical processing functionalities. In optical sensing, the device could respond to ultraviolet (UV) light with low intensity down to microwatts per square centimeter, representing so far the most UV-sensitive nonvolatile optoelectronic neural device. In electrical-processing, the PENT demonstrates a mechanically immediate switchable plasticity between short-term and long-term by altering charge carriers in the conductive channel; this emulates the selective release of different neurotransmitters, i.e. dopamine and noradrenaline, from a same axon, for pain-avoiding and pleasure-inducing patterns of Skinner Box for the first time. Furthermore, a new strategy for gesture recognition was developed. This approach can be applied to control and design multipurpose neuromorphic systems by combining brain-like processing and artificial sensory nerves.
Multiplexed neurotransmission emulated for emotion control
2021, Nano Energy
Citation Excerpt :
Forms of AER mainly include automatic cognitive change [3–6], automatic attentional control [7,8], and automatic behavior control [9,10]. The ability of our brain to select an appropriate AER strategy and subsequent response to a complex external environment requires multiplexed neurotransmission of different neurotransmitters, i.e. co-release and co-transmission of glutamate and acetylcholine from distinct microdomain of the same axon, has recently been found to underlie deserve functions of ventral tegmental area (VTA) region in striatal interneurons or medial habenula neurons [11–16]. Different combinations of neurotransmitters could be released from various subgroups of VTA neurons to convey different information in a neural circuit [15,16].
Emotions are closely related to multiplexed neurotransmission of glutamate and acetylcholine in the hippocampus, which are competitors and partners respectively. This paper demonstrates the first hetero-junction two-dimensional dual-excitatory artificial synapse (AS) for mimicking co-release of the two different neurotransmitters. This AS for the first time presents an immediate switchable plasticity between short-term of < 10 s and long-term of > 10⁵ s, as both avoidance tendency of negative stimuli and lasting memory of positive emotion. 10⁵ s represents so far the best long term memory of ion-regulated ASs. Inclusion of a fourth terminal as a monitor enables the emulation of automatic emotion regulation (AER). The AS array-based neural network achieves up to ~97% recognition accuracy for emotion-correlated electroencephalogram patterns; a new concept of early warning of negative emotions is proposed for monitoring mood changes, especially useful for babies and patients with mental disease, paving the way to future bio-inspired intelligent systems.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewThe roles of co-transmission in neural network modulation

Abstract

Section snippets

Proctolin distribution and actions

Many neurotransmitters converge onto the same current

Patterns of co-localization in identified projection neurons

Three proctolin-containing neurons elicit different STG motor patterns

Segregation of co-transmitter actions

Convergence and divergence of network targets in co-transmitter release

The role of convergence in state-dependent modulator action

Do distinct co-transmitter complements ensure distinct actions on the same circuit?

Concluding remarks

Acknowledgements

Physiol. Rev.

Experientia

Neuron

J. Neurosci.

J. Neurosci.

Life Sci.

J. Comp. Neurol.

Nature

Eur. J. Neurosci.

Modulation of neural networks for behavior

Annu. Rev. Neurosci.

From biophysics to models of network function

Annu. Rev. Neurosci.

Principles of rhythmic motor pattern generation

Physiol. Rev.

Analysing the functional consequences of transmitter complexity

Trends Neurosci.

A peptide as a possible transmitter in sympathetic ganglia of the frog

Proc. Natl. Acad. Sci. USA

Peptidergic transmission in sympathetic ganglia of the frog

J. Physiol. (Lond)

Peptide cotransmitter at a neuromuscular junction

Science

Physiological consequences of a peptide cotransmitter in a crayfish nerve-muscle preparation

J. Neurosci.

Multiple neuropeptides in cholinergic motor neurons of Aplysia: evidence for modulation intrinsic to the motor circuit

Proc. Natl. Acad. Sci. USA

Release of peptide transmitters from a cholinergic motor neuron under physiological conditions

Proc. Natl. Acad. Sci. USA

Frequency-dependent release of peptide cotransmitters from identified cholinergic motor neurons in Aplysia

Proc. Natl. Acad. Sci. USA

Neuropeptide cotransmitters released from identified cholinergic motor neurons in Aplysia

J. Neurosci.

The secretion of classical and peptide cotransmitters from a single presynaptic neuron involves a synaptobrevin-like molecule

J. Neurosci.

Peptide cotransmitter release from motorneuron B16 in Aplysia californica: costorage, corelease, and functional implications

J. Neurosci.

Costorage and corelease of modulatory peptide cotransmitters with partially antagonistic actions on the accessory radula closer muscle of Aplysia californica

J. Neurosci.

Release of peptide cotransmitters in Aplysia: regulation and functional implications

J. Neurosci.

Physiology and biochemistry of peptidergic cotransmission in Aplysia

J. Physiol. (Paris)

Release of LHRH is linearly related to the time integral of presynaptic Ca2+ elevation above a threshold level in bullfrog sympathetic ganglion

Neuron

Exocytosis in peptidergic nerve terminals exhibits two calcium-sensitive phases during pulsatile calcium entry

J. Neurosci.

Cholinergic neuromuscular synapses in Aplysia have low endogenous acetylcholinesterase activity and a high-affinity uptake system for acetylcholine

J. Neurosci.

Dale's hypothesis revisited: different neuropeptides derived from a common prohormone are targeted to different processes

Proc. Natl. Acad. Sci. USA

Chemical transmission between rat sympathetic neurons and cardiac myocytes developing in microcultures: evidence for cholinergic, adrenergic, and dual-function neurons

Proc. Natl. Acad. Sci. USA

Continuous repetitive stimuli are more effective than bursts for evoking LHRH release in bullfrog sympathetic ganglia

J. Neurosci.

The role of patterned burst and interburst interval on the excitation-coupling mechanism in the isolated rat neural lobe

J. Physiol.

Neurotransmitter modulation of the stomatogastric ganglion of decapod crustaceans

Modulatory control of multiple task processing in the stomatogastric nervous system

Aminergic modulation in lobster stomatogastric ganglion. I. Effects on motor pattern and activity of neurons within the pyloric circuit

J. Neurophysiol.

Aminergic modulation in lobster stomatogastric ganglion. II. Target neurons of dopamine, octopamine, and serotonin within the pyloric circuit

J. Neurophysiol

Dopamine modulation of transient potassium current evokes phase shifts in a central pattern generator network

J. Neurosci.

Review
The roles of co-transmission in neural network modulation

Release of LHRH is linearly related to the time integral of presynaptic Ca²⁺ elevation above a threshold level in bullfrog sympathetic ganglion