Month: November 2023

Essay 23: Feeding and Neuropeptide Core

On November 28, 2023

I like the model of motivation where the hypothalamus and midbrain structures like the ventral tegmental area (Vta), periaqueductal gray (M.pag), and parabrachial nucleus (B.pb) form the motivational core, primarily run by neuropeptides signaling, based on old chemical communication. [Damasio and Carvalho 2013] consider this area as an organized map for feelings, like the optic tectum (OT) has a retina-centric map for visual interest.

To avoid getting stuck in philosophical woo, I’m avoiding the question of whether this area is a primary source of feelings, but I like the idea of a semi-organized map at the base of motivation. The parabrachial nucleus (B.pb) is a good place to start, because its neurons encode warnings like pain, visceral summaries, and primitive feeding, including basic taste.

Parabrachial nucleus

B.pb provides a coarse summary of taste, pain, temperature, and visceral feelings like malaise without the details. It can report that something tastes good because it’s sweet or tastes bad because it’s bitter, but can’t experience chocolate. It’s more of an action-focused alarm [Campos et al. 2018] than a sensory experience.

For example, if B.pb detects bitter taste or malaise, it sends a general notice to other areas in the peptide core to stop eating and investigate further. If B.pb tastes sweet, it encourages eating. In addition to senses like taste and warning, B.pb has action control of its own, including reflexive escape actions, breathing and heart rate to the medulla (B.mdd) and B.nts. So, it can serve as a lower-level action hub.

B.pb and neuropeptides

B.pb poses an immediately difficulty for the simulation animal because it’s organized chemically by neuropeptides instead of a simple topological and connectivity map. The following diagram is a broad topographic map of B.pb [Chiang et al. 2019] that illustrates the issue.

*Topological map of the parabrachial nucleus.*

As shown above, the colored areas do not respect the named boundaries. The blue area represents taste neuron areas and the red area represents general alarm (pain, heat, cold, malaise, etc.) But even those colored areas are an oversimplification because neuron functions are mixed together salt-and-pepper style. [Pauli et al. 2022] found 21 subclusters of B.pb neuron peptide receptors and transmission, each of which may have distinct projection patterns.

This neuropeptide focus isn’t restricted to B.pb. The lateral hypothalamus (H.l), another major node in the feeding circuit, is also organized by neuropeptides, including important ones like orexin (exploring), and MCH, which it sends across the entire brain. Although [Diaz et al. 2023] has broken H.l into 9 areas, these may not be sufficient because of the neuropeptide focus. [Mickelsen et al. 2019] found 15 clusters of glutamate neurons and 15 clusters of GABA neurons. [Guillaumin and Burdakov 2017] and [Burdakov and Karnani 2020] find H.l functional communication through neuropeptides that are invisible to traditional synaptic communication.

Neuropeptide core

An “isodendritical core” [Ramón-Moliner and Nauta 1966] in the hypothalamus and midbrain is an old idea with a more modern description in [Agnati et al. 2010], which is a good starting point for the essay simulation. The core includes reticular areas of the hypothalamus, B.pb, M.pag, and the Vta (aka posterior tuberculum in zebrafish). “Neuropeptide core” matches my imagination of this area better than the old name. A diagram of the core is below, with the caveat that neuropeptide broadcasting is more important for communication than the diagram’s arrows.

As shown above, the neuropeptide core is highly interconnected. B.pb includes taste and visceral sensation like nausea together with visceral control. H.l includes blood sensors like glucose level, insulin, and fat and protein levels. M.pag includes many innate behaviors including freezing, flight and grooming. Vta controls actions, including seeking and searching.

As the diagram illustrates, the neural connectivity of the inner core is not particularly useful because they’re all entirely interconnected. For simplicity of the essay simulation, I’m using a model where the core neuropeptides are shared in a common neuropeptide soup, or canal, where the neuropeptide identity is more important than the neuron’s specific physical location. For example, treating B.pb as one or two areas instead of the seven areas above.

Cerebrospinal fluid as neuropeptide canal

The periventricular areas like H.pv and M.pag are named for their location around the ventricles, which contains cerebrospinal fluid (CSF). These areas contain neurons that directly sense neurotransmitters and neuropeptides in the CSF itself. The CSF can be a canal for transmitting neuropeptides [Bjorefeldt et al. 2018].

Earlier photo-vertebrate animals may have used a similar canal more extensively. Because of the smaller brain size, diffusion in the canal may have been sufficient for communication without point to point synapses. [Vigh et al. 2004] point out that amphioxus larva, a pre-vertebrate chordate, has much of its com munition in a single neuropile (intertwined dendrites and axons) that’s open to sea water until its neural tube closes as an adult.

Neuropeptides and timing

Neuropeptides act on a much slower timescale than faster neurotransmitters like glutamate and GABA. Glutamate and GABA synapse are a few microseconds and clear rapidly. Neuropeptides can persist tens of seconds to tens of minutes. For an animal’s motivation, like fleeing a predator, the longer timescale is more appropriate, because the animal shouldn’t stop fleeing if it loses sight of the predator for ten milliseconds or even a second or two. Similarly, foraging for food is a longer task measured in many minutes or hours, not milliseconds. The longer chemical timing of the peptides is more suited to motivational timing than the fast reactive transmitters.

Peptide circuits

I’ve sketched out some possible neuropeptide circuits for feeding are portrayed in the diagram below, organized by behavior.

The first diagram shows dopamine as a primary seeking neurotransmitter [Alcaro et al. 2007]. When the animal finds target by odor in the simulation, dopamine tells the Vta to connect the olfactory bulb (Ob) to the motor locomotive region (MLR), aiming the animal to the food scent.

The second shows orexin as a general food exploration signal. In contrast with the target-focused seeking, exploration is a random search.

The third is part of the eating circuit, where CGRP (an alarm neuropeptide) tonically inhibits eating, until AgRP (a hunger neuropeptide) disinhibits it [Essner et al. 2017].

References

Agnati, L. F., Guidolin, D., Guescini, M., Genedani, S., & Fuxe, K. (2010). Understanding wiring and volume transmission. Brain research reviews, 64(1), 137-159.

Alcaro A, Brennan A, Conversi D. The SEEKING Drive and Its Fixation: A Neuro-Psycho-Evolutionary Approach to the Pathology of Addiction. Front Hum Neurosci. 2021 Aug 12;15:635932.

Bjorefeldt A, Illes S, Zetterberg H, Hanse E. Neuromodulation via the Cerebrospinal Fluid: Insights from Recent in Vitro Studies. Front Neural Circuits. 2018 Feb 5;12:5.

Burdakov D, Karnani MM. Ultra-sparse Connectivity within the Lateral Hypothalamus. Curr Biol. 2020 Oct 19;30(20):4063-4070.e2.

Campos CA, Bowen AJ, Roman CW, Palmiter RD. Encoding of danger by parabrachial CGRP neurons. Nature. 2018 Mar 29;555(7698):617-622.

Chiang, M. C., Bowen, A., Schier, L. A., Tupone, D., Uddin, O., & Heinricher, M. M. (2019). Parabrachial Complex: A Hub for Pain and Aversion. The Journal of neuroscience : the official journal of the Society for Neuroscience, 39(42), 8225-8230.

Damasio A, Carvalho GB. The nature of feelings: evolutionary and neurobiological origins. Nat Rev Neurosci. 2013 Feb;14(2):143-52.

Diaz, C., de la Torre, M.M., Rubenstein, J.L.R. et al. Dorsoventral Arrangement of Lateral Hypothalamus Populations in the Mouse Hypothalamus: a Prosomeric Genoarchitectonic Analysis. Mol Neurobiol 60, 687–731 (2023).

Essner RA, Smith AG, Jamnik AA, Ryba AR, Trutner ZD, Carter ME. AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons. J Neurosci. 2017 Sep 6;37(36):8678-8687.

Guillaumin MCC, Burdakov D. Neuropeptides as Primary Mediators of Brain Circuit Connectivity. Front Neurosci. 2021 Mar 11;15:644313.

Mickelsen LE, Bolisetty M, Chimileski BR, Fujita A, Beltrami EJ, Costanzo JT, Naparstek JR, Robson P, Jackson AC. Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons. Nat Neurosci. 2019 Apr;22(4):642-656.

Pauli JL, Chen JY, Basiri ML, Park S, Carter ME, Sanz E, McKnight GS, Stuber GD, Palmiter RD. Molecular and anatomical characterization of parabrachial neurons and their axonal projections. Elife. 2022 Nov 1;11:e81868.

Pessoa L, Medina L, Desfilis E. Refocusing neuroscience: moving away from mental categories and towards complex behaviours. Philos Trans R Soc Lond B Biol Sci. 2022 Feb 14;377(1844):20200534.

Ramón-Moliner E, Nauta WJ. The isodendritic core of the brain stem. J Comp Neurol. 1966 Mar;126(3):311-35.

Vígh B, Manzano e Silva MJ, Frank CL, Vincze C, Czirok SJ, Szabó A, Lukáts A, Szél A. The system of cerebrospinal fluid-contacting neurons. Its supposed role in the nonsynaptic signal transmission of the brain. Histol Histopathol. 2004 Apr;19(2):607-28.

Essay 22 issues: subthalamic nucleus simulation

By ferg

On November 14, 2023

In Uncategorized

The essay 22 simulation explored a striatum model where the two decision paths competed: odor seeking vs random exploration, using dopamine to bias between exploration and seeking. This model resembled striatum theories like [Bariselli et al. 2020] that consider the stratum’s direct and indirect paths as competing between approach and avoidant actions.

Issues in essay 22 include both neuroscience divergence and simulation problems. Although the simulation is a loose functional model, that laxity isn’t infinite and it may have gone too far from the neuroscience.

Adenosine and perseveration

Seeking and foraging have a perseveration problem: the animal must eventually give up on a failed cue, or it will remain stuck forever. The give-up circuit in essay 22 uses the lateral habenula (Hb.l) to integrate search time until it reaches a threshold to give up. An alternative circuit in the stratum itself involves the indirect path (S.d2), the D2 dopamine receptor and adenosine, with a behaviorally relevant time scale.

When fast neurotransmitters are on the order of 10 milliseconds, creating a timeout on the order of a few minutes is a challenge. Two possible solutions in that timescale are long term potentiation (LTP) where “long” means about 20 minutes, and astrocyte calcium accumulation, which is also about 10 to 20 minutes.

Adenosine receptors (A2r) in the striatum indirect path (S.d2) measure broad neural activity from ATP byproducts that accumulate in the intercellular space. Over 10 minutes those A2r can produce internal calcium ion (Ca) in the astrocytes or via LTP to enhance the indirect path. Enhancing the indirect path (exploration), eventually causes a switch from the direct path (seeking) to exploration, essentially giving-up on the seeking.

Ventral striatum

Although the essay models the dorsal striatum (S.d), the ventral striatum (S.v aka nucleus accumbens) is more associated with exploration and food seeking. In particularly, the olfactory path for food seeking goes through S.v, while midbrain motor actions use S.d. In salamanders, the striatum only processes midbrain (“collo-“) thalamic inputs, while olfactory and direct senses (“lemno-“) go to the cortex [Butler 2008]. Assuming the salamander path is more primitive, the essay’s use of S.d in the model is a likely mistake.

But S.v raises a new issue because S.v doesn’t use the subthalamus (H.stn) [Humphries and Prescott 2009]. Although, that model only applies to the S.v shell (S.sh) not the S.v core (S.core).

*Ventral striatum pathway. MLR midbrain locomotive region, P.v ventral pallidum, S.sh ventral striatum shell, Vta ventral tegmental area.*

In the above diagram of a striatum shell circuit, an odor-seek path is possible through the ventral tegmental area (Vta) but there is no space for an alternate explore path.

Low dopamine and perseveration

[Rutledge et al. 2009] investigates dopamine in the context of Parkinson’s disease (PD), which exhibits perseveration as a symptom. In contrast to the essay, PD is a low dopamine condition, and adding dopamine resolves the perseveration. But that resolve is the opposite of essay 22’s dopamine model, where low dopamine resolved perseveration.

Now, it’s possible that give-up perseveration and Parkinson’s perseveration are two different symptoms, or it’s possible that the complete absence of dopamine differs from low tonic dopamine, but in either case, the essay 22 model is too simple to explain the striatum’s dopamine use.

Dopamine burst vs tonic

Dopamine in the striatum has two modes: burst and tonic. Essay 22 uses a tonic dopamine, not phasic. The striatum uses phasic dopamine to switch attention to orient to a new salient stimulus. The phasic dopamine circuit is more complicated than the tonic system because it requires coordination with acetylcholine (ACh) from the midbrain laterodorsal tegmentum (V.ldt) and pedunculopontine (V.ppt) nuclei.

A question for the essays is whether that phasic burst is primitive to the striatum, or a later addition, possibly adding an interrupt for orientation to an earlier non-interruptible striatum.

Explore semantics

The word “explore” is used differently by behavioral ecology and in reinforcement learning, despite both using foraging-like tasks. These essays have been using explore in the behavioral ecology meaning, which may cause confusion on the reinforcement learning sense. The different centers on a fixed strategy (policy) compared with changing strategies.

In behavioral ecology, foraging is literal foraging, animals browsing or hunting in a place and moving on (giving up) if the place doesn’t have food [Owen-Smith et al. 2010]. “Exploring” is moving on from an unproductive place, but the policy (strategy) remains constant because moving on is part of the strategy. The policy for when to stay and when to go [Headon et al. 1982] often follows the marginal value theorem [Charnov 1976], which specifies when the animal should move on.

In contract, reinforcement learning (RL) uses “explore” to mean changing the policy (strategy). For example, in a two-armed bandit situation (two slot machines), the RL policy is either using machine A or using machine B, or a fixed probabilistic ratio, not a timeout and give-up policy. In that context, exploring means changing the policy not merely switching machines.

[Kacelnick et al. 2011] points out that the two-choice economic model doesn’t match vertebrate animal behavior, because vertebrates use an accept-reject decision [Cisek and Hayden 2022]. So, while the two-armed bandit may be useful in economics, it’s not a natural decision model for vertebrates.

Avoidance (nicotinic receptors in M.ip)

The simulation uncovered a foraging problem, where the animal remained around an odor patch it had given up on, because the give-up strategy reverts to random search. Instead, the animal should leave the current place and only resume search when its far away.

*Path of simulated animal after giving up on a food odor.*

In the diagram above, the animal remains near the abandoned food odor. The tight circles are the earlier seek before giving up, and the random path afterwards is the continued search. A better strategy would leave the green odor plume and explore other areas of the space.

As a possible circuit, the habenula (Hb.m) projects to the interpeduncular nucleus (M.ip) uses both glutamate and ACh as neurotransmitters, where ACh amplifies neural output. For low signals without ACh, the animal approaches the object, but high signals with ACh switch approach to avoidance. This avoidance switching is managed by the nicotine receptor (each) which is studied for nicotine addiction [Lee et al. 2019].

An interesting future essay might explore using nicotinic aversion to improve foraging by leaving an abandoned odor plume.

References

Bariselli S, Fobbs WC, Creed MC, Kravitz AV. A competitive model for striatal action selection. Brain Res. 2019 Jun 15;1713:70-79.

Butler, Ann. (2008). Evolution of the thalamus: A morphological and functional review. Thalamus & Related Systems. 4. 35 – 58.

Charnov, Eric L. Optimal foraging, the marginal value theorem. Theoretical population biology 9.2 (1976): 129-136.

Cisek P, Hayden BY. Neuroscience needs evolution. Philos Trans R Soc Lond B Biol Sci. 2022 Feb 14;377(1844):20200518.

Headon T, Jones M, Simonon P, Strummer J (1982) Should I Stay or Should I Go. On Combat Rock. CBS Epic.

Humphries MD, Prescott TJ. The ventral basal ganglia, a selection mechanism at the crossroads of space, strategy, and reward. Prog Neurobiol. 2010 Apr;90(4):385-417.

Kacelnik A, Vasconcelos M, Monteiro T, Aw J. 2011. Darwin’s ‘tug-of-war’ vs. starlings’ ‘horse-racing’: how adaptations for sequential encounters drive simultaneous choice. Behav. Ecol. Sociobiol. 65, 547-558.

Lee HW, Yang SH, Kim JY, Kim H. The Role of the Medial Habenula Cholinergic System in Addiction and Emotion-Associated Behaviors. Front Psychiatry. 2019 Feb 28

Owen-Smith N, Fryxell JM, Merrill EH. Foraging theory upscaled: the behavioural ecology of herbivore movement. Philos Trans R Soc Lond B Biol Sci. 2010 Jul 27;365(1550):2267-78.

Rutledge RB, Lazzaro SC, Lau B, Myers CE, Gluck MA, Glimcher PW. Dopaminergic drugs modulate learning rates and perseveration in Parkinson’s patients in a dynamic foraging task. J Neurosci. 2009 Dec 2