essays on mind

Attempting a toy model of vertebrate understanding

Month: October 2023

Essay 22: Subthalamic Nucleus

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On October 29, 2023

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After essay 21 changed the animal’s default movement to a Lévy exploration, it’s immediate to ask whether that random search is a full action, just like a seek turn or an avoid turn. An if exploration is a controlled action, then the model needs to treat exploration as a full action, like approach or avoid.

Exploration as a full locomotive system at the level of approach and avoid.

[Cisek 2020] identifies a vertebrate system for exploration, including the hippocampus (E.hc) and its associated nuclei such as the retromammilary hypothalamus (H.rm aka supramammilary). Essay 22 considers the idea of treating the subthalamic nucleus (H.stn) as part of the exploration circuit.

Subthalamic nucleus

H.stn is a hypothalamic nucleus from the same area as H.rm, which is part of the hippocampal theta circuit, which synchronizes exploration and spatial memory and learning. However, H.stn is part of the basal ganglia and not directly connected with the exploration system.

[Watson et al. 2021] finds a locomotive function of H.stn, where specific stimulation by the parafascicular thalamus (T.pf) to H.stn starts locomotion. If the stimulation is one-sided, the animal moves forward with a wide turn to the contralateral side. T.pf includes efference copies of motor actions from the MLR as well as from other midbrain actions.

Locomotion induced in the H.stn by T.pf stimulation. H.stn sub thalamic nucleus, T.pf parafascicular nucleus, MLR midbrain locomotor region.

For essay 22, let’s consider the H.stn locomotion as exploration. Since H.stn is part of the basal ganglia, the bulk of essay 22 is considering how exploration might fit into the proto-striatum model of essay 18.

Striatal attention and persistence

Since the current essay simulation animal is an early Cambrian proto-vertebrate, it doesn’t have a full basal ganglia. Evolutionarily, the full basal ganglia architecture could not have sprung into being fully formed; it must have developed in smaller step. Following a hypothetical evolutionary path, the essays are only implementing a simplified striatal model, adding features step-by-step. Unfortunately, because there’s no living species with a partial basal ganglia — all vertebrates have the full system — the essay’s steps are pure invention.

The initial striatum of essay 18 was a partial solution to a simulation problem: persistence. When the animal hit a wall head on, activating both touch sensors, it would choose randomly left or right, but because the simulation is real-time not turn-based, at the next tick both sensors remained active and the animal would choose randomly again, jittering at the wall until enough turns of the same direction escaped the barrier.

proto-striatum circuit for persistence by attention.
Proto-striatum for persistence by attention. Action feedback biases the choice to the last option: win-stay. B.rs reticulospinal motor command, Ob olfactory bulb, MLR midbrain locomotor region, Snc substantia nigra pars compacta (posterior tuberculum).

The main sense-to-action path is from the olfactory bulb (O.b) through the substantia nigra (Snc aka posterior tuberculum in zebrafish) to the midbrain locomotor region (MLR) and to the reticulospinal motor command neurons (B.rs), following the tracing and locomotive study of [Derjean et al. 2010] in zebrafish and Vta/Snc control of locomotion in [Ryczko et al. 2017]. The proto-striatum circuit is built around that olfactory-seeking circuit, acting persistent attention.

The proto-striatal model uses an efference copy of the last action from the MLR to bias the choice of the next action via a MLR to T.pf to striatum path. The model biases the choice through removing inhibition of the odor to action path. If the last action as left, the left odor is disinhibited, making it more likely to win.

The striatal system uses disinhibition for noise reasons. [Cohen et al. 2009] studied attention in the visual system and found that attention removed coherent noise by removing inhibition. By removing inhibition, the attended circuit is less affected by the controlling circuit’s noise.

Note: essay 19 considered an alternative solution to the attention issue by following the nucleus isthmi system in zebrafish as studied in [Grubert et al. 2006], where the attention to the win-stay odor used acetylcholine (ACh) amplification to bias the choice.

Striatal columns: approach and avoid

An immediate difficulty with the simple proto-striatal model is the lack of priority. Although left vs right have equal priority, avoiding a predator is more important than seeking a potential food source. Unfortunately, the proto-striatum treats all options equally. As a solution, essay 18 split the striatum into columns, where each column resolves an internal conflict without priority (“within-system”) and the columns are compared separately (“between-systems”), where “within-system” and “between-system” are from [Cisek 2019].

Proto-striatum columns for maintaining attention.
Dual striatum column for approach and avoid, where MLR resolves the final conflict. B.rs reticulospinal command neuron, B.ss somatosensory (touch), MLR midbrain locomotive region, M.pag periaqueductal gray, Ob olfactory bulb, S.ot olfactory tubercle, S.d dorsal striatum.

Subthalamic nucleus and exploration

If we now treat exploration as a distinct action system, then it needs its own control system and column in the proto-striatum. The within-system choice for exploration is the left and right turns for a random walk, and the between-system choices are between the exploration system and the odor-seeking system.

As a possible neural correlate of exploration, consider the sub thalamic nucleus (H.stn). The sub thalamic nucleus is derived from the hypothalamus, specifically from the same area as the retromammilary area (H.rm aka supramammilary), which is highly correlated with hippocamptal theta, locomotion and exploration.

[Watson et al. 2021] finds a locomotive function of H.stn, where specific stimulation by the parafascicular thalamus (T.pf) produces locomotion via the midbrain locomotive region (MLR). T.pf includes efference copies of motor actions from the MLR as well as other midbrain action efference copies. In the proto-striatum model, the feedback from MLR to striatum uses T.pf.

Exploration locomotive path through H.stn. H.stn sub thalamic nucleus, MLR midbrain locomotive region, T.pf parafascicular thalamus.

Seek and explore with dual striatal columns

Suppose the striatum manages both odor seeking (chemotaxis) and default exploration (Lévy walk). The two actions are conflicting with a complex priority system. When a food odor first appears, the animal should seek toward it (priority to seek), but if no food exists the animal should resume exploration (priority to explore). To resolve the between-system conflict, the two strategies need to columns with lateral inhibition to ensure that only one is selected.

Dual striatum columns for seek and explore strategies. B.rs reticulospinal motor command, H.stn sub thalamic nucleus, Ob olfactory bulb, P.ge globus pallidus external, S.d1 direct striatum projection, S.d2 indirect striatum projection, Snc substantia nigra pars compacta, Snr substantia nigra pars reticulata.

Selecting the seek column enables the odor sense to MLR path, seeking the potential food odor. Selecting the explore column enables the H.stn to MLR path, randomly searching for food.

Note: the double inversion in both paths is to reduce neuron noise [Cohen et al. 2009]. Removing inhibition reduces noise, where adding excitation would add noise. In the essay stimulation, this double negation isn’t necessary.

Striatum with dopamine/habenula control

The previous dual column circuit isn’t sufficient for the problem, because it lacks a control signal to switch between exploit (seek) and explore. The striatum dopamine circuit might help this problem by bringing in the foraging implementation from essay 17.

A major problem in essay 17 was the tradeoff between persistence and perseverance in seeking an odor. Persistence ensures that seeking an odor will continue even when the intermittent. Perseverance is a failure mode where the animal never gives up, like a moth to a flame. As a model, consider using dopamine in the striatum as persistence or effort [Salamone et al. 2007], and control of dopamine by the habenula as solving perseverance with a give-up circuit.

Explore and exploit (seek) columns controlled by dopamine. H.l lateral hypothalamus, Hb.l lateral habenula, H.stn sub thalamic nucleus, MLR midbrain locomotive region, Ob olfactory bulb, P.em pre thalamic eminence, P.ge globus pallidus external, S.d1 striatum direct projection, S.d2 striatum indirect projection, Snc substantia nigra pars compacta, Snr substantia nigra pars reticulata.

The striatum uses two opposing dopamine receptors named D1 and D2. D1 is a stimulating modulator though a G.s protein path, and D2 is an inhibiting modulator through a G.i protein path. In the above diagram, high dopamine will activate the seek column via D1 and inhibiting the explore column via D2. Low dopamine inhibits the seek column and enables the explore column. So dopamine becomes an exploit vs explore controller.

In many primitive animals, dopamine is a food signal. In c.elegans the dopamine neuron is a food-detecting sensory neuron. In vertebrates, the hunger and food-seeking areas like the lateral hypothalamus (H.l) strongly influence midbrain dopamine neurons both directly and indirectly. Indirectly, H.l to lateral habenula (Hb.l) causes non-reward aversion [Lazaridis et al. 2019].

For the essay, I’m taking H.l as multiple roles (H.l is a composite area with at least nine sub-areas [Diaz et al. 2023]), both calculating potential reward (odor) via the H.l to Vta/Snc connection, and cost (exhaustion of seek task without success) via the H.l to Hb.l to Vta/Snc connection.

References

Cisek P. Resynthesizing behavior through phylogenetic refinement. Atten Percept Psychophys. 2019 Oct

Cisek P. Evolution of behavioural control from chordates to primates. Philos Trans R Soc Lond B Biol Sci. 2022 Feb 14

Cohen MR, Maunsell JH. Attention improves performance primarily by reducing interneuronal correlations. Nat Neurosci. 2009 Dec;12(12):1594-600.

Derjean D, Moussaddy A, Atallah E, St-Pierre M, Auclair F, Chang S, Ren X, Zielinski B, Dubuc R. A novel neural substrate for the transformation of olfactory inputs into motor output. PLoS Biol. 2010 Dec 21

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).

Gruberg E., Dudkin E., Wang Y., Marín G., Salas C., Sentis E., Letelier J., Mpodozis J., Malpeli J., Cui H. Influencing and interpreting visual input: the role of a visual feedback system. J. Neurosci. 2006;26:10368–10371

Lazaridis I, Tzortzi O, Weglage M, Märtin A, Xuan Y, Parent M, Johansson Y, Fuzik J, Fürth D, Fenno LE, Ramakrishnan C, Silberberg G, Deisseroth K, Carlén M, Meletis K. A hypothalamus-habenula circuit controls aversion. Mol Psychiatry. 2019 Sep

Ryczko D, Grätsch S, Schläger L, Keuyalian A, Boukhatem Z, Garcia C, Auclair F, Büschges A, Dubuc R. Nigral Glutamatergic Neurons Control the Speed of Locomotion. J Neurosci. 2017 Oct 4

Salamone JD, Correa M, Nunes EJ, Randall PA, Pardo M. The behavioral pharmacology of effort-related choice behavior: dopamine, adenosine and beyond. J Exp Anal Behav. 2012 Jan

Watson GDR, Hughes RN, Petter EA, Fallon IP, Kim N, Severino FPU, Yin HH. Thalamic projections to the subthalamic nucleus contribute to movement initiation and rescue of parkinsonian symptoms. Sci Adv. 2021 Feb 5

Essay 21: Syllables and Lévy walks

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On October 19, 2023

In Uncategorized

Previous essays used a simple default ballistic forward motion action: the animal moved forward until it hit an obstacle or encountered food or an odor plume. Furthermore, all actions in the essay were continuous: at every time-step direction or speed could change. The animal was slug-like. However, since vertebrate is oscillatory — swimming or walking — powered by central pattern generators (CPGs), vertebrate motor commands are not continuous but modifiable only on correct timing of the oscillatory cycle.

This essay 21 adds some more realism to the simulated animal by creating distinct action syllables, each of which runs to completion. In addition, the default movement is a Lévy walk to more efficiently search for food.

Zebrafish bouts and mouse modules

Zebrafish larva move in discrete bouts [Johnson et al. 2020], punctuated by pauses. Each bout is on the order of 200ms to 1000ms and consists of stereotyped movement like a forward swimming stroke, and several turn types possibly followed by forward motion. The neural source of the bout timing is not know, although basal ganglia (striatal) defects can also produce jerky motion instead of smoothly linked motion.

Mouse movement is also comprised of small modules [Wiltschko et al. 2016] on the order of 60 modules in open exploration, each module lasting 200ms to 500ms. Unlike the zebrafish larva, sequences of mouse modules are linked smoothly instead of in jerky bouts.

Simulation action syllables

To match the vertebrate action syllables, the essay simulation now has action syllables at the lowest layers. The action syllables are fixed programs that last for several simulation ticks. For example a forward left turn might take 10 simulation ticks, depending on the tick resolution. In other words, these syllables are more like real-time actions with limited time resolution, not turn-based actions like a board game.

Unlike the current action completes, the system ignores new neural commands. In the future, specialized commands like freeze or panic escape might override the current action, like fast escape of zebrafish that bypass normal motor logic. In theory the system could also incorporate mid-action modulation, such as adding power to a swimming stroke without altering the basic action.

The new syllables should add realism and also introduce complications that vertebrates need to solve, such as timing for sequences of syllables. The syllables also introduce issues because prior-action memory as modeled by the striatum and nucleus isthmi need to persist for a syllable, not just a simulation tick.

Lévy walks

Along with the syllable changes, essay 21 adds better default movement. Previously if the animal wasn’t approaching food or avoiding an obstacle, it would move forward ballistically. That simplification only worked because the simulation is a simple bounded box, but in nature animals have better default search strategies.

Brownian motion is a simple default. The animal turns a random direction, then moves forward a random (gaussian) distance. Brownian motion does well at searching a neighborhood and is better than the essay’s ballistic strategy, but it tends to get stuck in a small area. When food is scarce and patchy, the brownian strategy won’t move the long distances needed to effectively find a new patch. The Lévy walk improves on this strategy by moving long distances when the current neighborhood is already searched [Abe 2020].

Default random walk for the simulated animal.

A Lévy walk is fractal (“scale-free”): larger walks have the same search structure as neighborhood search. If described in probabilistic terms, the distance traveled looks like a power law:

P(len) = 1/ len ^ 2

Where the exponent 2 (alpha) can be generalized between 1 and 3. The bounds are because the exponent 1 or less is ballistic and exponent 3 or more is essentially brownian. If alpha is closer to 1, the search is wider and moving further, while an alpha is closer to 3, the search is closer and more local.

Central pattern generators, criticality, and chaos

Animals do seem to use Lévy walks [Kölzsch et al. 2015] and the source appears to be internally generated [Berni et al. 2012] as opposed to a response to a fractal environment. The internal source of the randomness is not well know, although central pattern generators appear to be a possibility [Sims et al. 2018], [Reynolds 2019].

Near a critical point, fractal patterns appear and can be efficient computationally [Abe 2020], and a relatively simple chaotic system with only two random variables and produce Lévy walks. More broadly, other brain areas such as the cortex may also use criticality or near criticality to improve computation and generate longer-lasting signals to solve the timing problem [Hidalgo et al. 2014]. The timing problem is that fast neurons are 10ms but behavior needs to be responsive on the order of seconds and minutes.

Vertebrate source of Lévy walks

Although there is some knowledge of the search circuitry in fruit flies [Berni et al. 2012], the vertebrate circuitry seems entirely unknown.

As a thought experiment, consider the midbrain theta circuitry as part of the exploration circuit [Cisek 2022], and therefore related to the Lévy walk. If the vertebrate search is generated by a combination of central pattern generators then the source should be in the hindbrain, near those CPGs.

Midbrain and hindbrain theta circuitry. B.ni nucleus incepts, B.pno nucleus pontus oralis, B.rs reticulospinal motoc neurons, B.vtn ventral tegmental nucleus, H.rm retromammilary (supramammilary), Hb.m medial habenula, M.ip interpeduncular nucleus, P.ms medial septum, Poa preoptic area, V.mr median raphe.

Theta clock cycles (4-12hz) in the brain are strongly correlated with exploratory movement, thought, and learning especially with the hippocampus (E.hc).

In the above, the hindbrain contains the chaotic search circuitry and generates theta, such as B.pno and B.vtn in conjunction with the reticulospinal motor command (B.rs). B.vtn is the forward movement analogue of the head direction nucleus B.dtn.

The medial septum (P.ms) is essentially the main theta clock for the hippocampus. Part of the theta cycle is generated internally to P.ms with spontaneous interaction of acetylcholine (ACh) and GABA inhibitory neurons, but exploration-related theta comes from the hypothalamic retromammilary (H.rm, aka supramammilary), which receives its theta from the hindbrain theta centers.

The movement restriction for theta depends on the median raphe (V.mr), which is one of the two main serotonin (5HT) centers. If V.mr is disabled, theta through H.rm always exists, not restricted to exploration. V.mr is in turn strongly influenced with the habenula (Hb.m) and interpeduncular (M.ip) complex.

Simulation

For now, I’m avoiding using criticality or chaotic variables in the simulation, although criticality is an interesting design to explore and very possibly how the vertebrate brain solves these problems.

The disadvantage is that the simulation would quickly become unclear and overcomplicated. While a few chaotic variables in the brainstem might be manageable, extending that idea to the striatum and cortex seems like it would become impenetrable. Since the purpose of the simulation is something like an executable thought experiment or executable diagram, and impenetrable simulation is defeating the purpose. Some alternatives like [Bartumeus and Levin 2008] fractal reorientation clocks might serve the purpose while remaining more clear.

References

Abe MS. Functional advantages of Lévy walks emerging near a critical point. Proc Natl Acad Sci U S A. 2020 Sep 29

Bartumeus F, Levin SA. Fractal reorientation clocks: Linking animal behavior to statistical patterns of search. PNAS. 2008

Berni J., Pulver S.R., Griffith L.C., Bate M. Autonomous circuitry for substrate exploration in freely moving Drosophila larvae. Curr. Biol. 2012

Berni J., Genetic dissection of a regionally differentiated network for exploratory behavior in Drosophila larvae. Curr. Biol. 25, 1319–1326 (2015).

Cisek P. Evolution of behavioural control from chordates to primates. Philos Trans R Soc Lond B Biol Sci. 2022 Feb 14

Hidalgo J, Grilli J, Suweis S, Muñoz MA, Banavar JR, Maritan A. Information-based fitness and the emergence of criticality in living systems. Proc Natl Acad Sci U S A. 2014 Jul 15

Kölzsch A., et al., Experimental evidence for inherent Lévy search behaviour in foraging animals. Proc. R. Soc. B Biol. Sci. 282, 20150424 (2015)

Maass W, Natschläger T, Markram H. Real-time computing without stable states: a new framework for neural computation based on perturbations. Neural Comput. 2002 Nov

Nurzaman SG, Matsumoto Y, Nakamura Y, Shirai K, Koizumi S, Ishiguro H. From Lévy to Brownian: a computational model based on biological fluctuation. PLoS One. 2011 Feb 3

Reynolds A. M., Current status and future directions of Lévy walk research. Biol. Open 7, bio030106 (2018)

Sims DW, Reynolds AM, Humphries NE, Southall EJ, Wearmouth VJ, Metcalfe B, Twitchett RJ. Hierarchical random walks in trace fossils and the origin of optimal search behavior. Proc Natl Acad Sci U S A. 2014 Jul 29

Sims D. W., Humphries N. E., Hu N., Medan V., Berni J., Optimal searching behaviour generated intrinsically by the central pattern generator for locomotion. eLife 8, e50316 (2019)

Wiltschko AB, Johnson MJ, Iurilli G, Peterson RE, Katon JM, Pashkovski SL, Abraira VE, Adams RP, Datta SR. Mapping Sub-Second Structure in Mouse Behavior. Neuron. 2015 Dec 16

Wolf S, Nicholls E, Reynolds AM, Wells P, Lim KS, Paxton RJ, Osborne JL. Optimal search patterns in honeybee orientation flights are robust against emerging infectious diseases. Sci Rep. 2016 Sep 12

Essay 20: Olfactory avoidance

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On October 16, 2023

In Uncategorized

Although the essays have implemented obstacle avoidance, they haven’t yet explored olfactory avoidance. Olfactory avoidance is distinct from obstacles, not just because obstacles have higher priority, but because the olfactory system is from an entirely different nervous system than the sensorimotor system. In the chimaeral brain theory [Tosches and Arendt 2013], bilaterian brains are composed of an apical nervous system (ANS) focused on chemo senses (olfactory external and hypothalamic internal), and a blastoporal nervous system (BNS) focused on sensorimotor control like obstacle avoidance.

Olfactory path

The paths for olfactory motion compared with obstacle motion shows the value of the chimaeral theory in making sense of the brain. Working backward from the midbrain locomotive region (MLR), the acetylcholine (ACh) MLR nuclei specialize: the pedunculopontine nucleus (M.ppt) supports the sensorimotor BNS, and the laterodorsal tegmental nucleus (M.ldt) supports the chemosensory ANS.

Sensor-locomotion paths: olfactory on top and somatosensory on bottom. B.ll lateral line, B.rs reticulospinal motor command, B.ss somatosensory, Hb.m medial habenula, M.ldt laterodorsal tegmental nucleus, M.ppt pedunculopontine nucleus, Ob.m medial olfactory bulb, OT tectum, R.vis visual input, ,Vta ventral tegmental area.

In the above diagram, food odors and warning odors use distinct paths to the MLR. Food odors from the olfactory bulb (Ob) pass through the ventral tegmental area (Vta – posterior tuberculum in zebrafish) to the MLR [Derjean et al. 2010]. Aversive odors like cadaverine pass through the medial habenula (Hb.m) to the M.ldt portion of the MLR [Stephenson-Jones et al. 2012]. The food and avoidance paths are distinct because hunger and satiety from the hypothalamus modulate the food path, while the avoidance path can pass through unmodulated. These olfactory locomotion paths correspond to the ANS.

Lamprey medial habenula path

All vertebrates share this basic architecture, including the lamprey, one of the most evolutionary-distant vertebrates. [Stephenson-Jones et al. 2012] traced the Hb.m circuit, showing that Hb.m inputs are from the olfactory path, the parapineal (light attraction), and an electron-sensory alarm to the interpeduncular nucleus (M.ip).

Lamprey olfactory warning path through the habenula to the MLR. M.ip interpeduncular nucleus.

The above diagram fills out the olfactory warning path. The interpeduncular nucleus is a key node in the avoidance circuit, and also key to locomotor-induced theta, and one of the two serotonin nodes. Mip has a major output to the serotonin areas: dorsal raphe (V.dr) and medial raphe (V.mr) and to the central grey (M.pag) [Quina et al. 2017] and M.ldt as well as structures associated with hippocampal (E.hc) theta [Lima et al. 2017].

Medial habenula behavior

In larval zebrafish, Hb.m supports olfactory avoidance [Choi et al. 2017], [Jeong et al. 2021], and light seeking [Zhang et al. 2017]. At least one study indicates that it may also affect food seeking [Chen et al. 2019]. The non-Ob input to Hb.m — the posterior septum (P.ps) — produce locomotion when stimulated [Ostu et al. 2018], suggesting that later evolved functionality maintains the original basal function.

In zebrafish, M.ip only projects to serotonin areas (V.dr and V.mr), not to dopamine or MLR areas. The lamprey connectivity suggests that the M.ip to M.ldt connection was lost in fish.

The Hb.m to M.ip connection is affected by nicotine. An interesting property is that low stimulation and high stimulation have opposite effects. Low stimulation uses glutamate connections and is attractive while high stimulation adds ACh and is aversive [Krishnan et al. 2014].

Developmental genetic notes

As an interesting aside, both Hb.m and avoidant layers of OT shared a genetic marker Brn3a (aka pou4f1) [Quina et al. 2009], [Fedtsova et al. 2008]. That marker also appears in the cerebellum’s inferior olive, trigeminal sensory areas, and the amphioxus motor LPN3 neuron [Bozzo et al. 2023].

M.ldt and M.ppt are sibling areas, deriving from the r1 rhombic lip [Machold et al. 2011].

Glutamate and GABA neurons in M.ip, Vta, and M.ldt all derive from r1 basal neurons [Lahti et al. 2016].

Locomotion switchboard

The addition of olfactory avoidance further complicates the switchboard combining the various locomotor streams, especially if the olfactory path uses serotonin as a modulator as opposed to a straight glutamate connection. Although I’ll probably use a fixed priority for essay 20, and as [Cisek 2022] notes, avoidance can be combined additively, at some point the switchboard will need more control, especially when essays add vision and consummatory actions.

References

Bozzo M, Bellitto D, Amaroli A, Ferrando S, Schubert M, Candiani S. Retinoic Acid and POU Genes in Developing Amphioxus: A Focus on Neural Development. Cells. 2023 Feb 14

Chen W-Y, Peng X-L, Deng Q-S, Chen M-J, Du J-L, Zhang B-B. Role of Olfactorily Responsive Neurons in the Right Dorsal Habenula-Ventral Interpeduncular Nucleus Pathway in Food-Seeking Behaviors of Larval Zebrafish. Neuroscience. 2019

Choi JH, Duboue ER, Macurak M, Chanchu JM, Halpern ME. Specialized neurons in the right habenula mediate response to aversive olfactory cues. Elife. 2021 Dec 8

Cisek P. Evolution of behavioural control from chordates to primates. Philos Trans R Soc Lond B Biol Sci. 2022 Feb 14

Derjean D, Moussaddy A, Atallah E, St-Pierre M, Auclair F, Chang S, Ren X, Zielinski B, Dubuc R. A novel neural substrate for the transformation of olfactory inputs into motor output. PLoS Biol. 2010 Dec 21

Fedtsova N, Quina LA, Wang S, Turner EE. Regulation of the development of tectal neurons and their projections by transcription factors Brn3a and Pax7. Dev Biol. 2008 Apr 1

Jeong YM, Choi TI, Hwang KS, Lee JS, Gerlai R, Kim CH. Optogenetic Manipulation of Olfactory Responses in Transgenic Zebrafish: A Neurobiological and Behavioral Study. Int J Mol Sci. 2021 Jul 3

Krishnan S, Mathuru AS, Kibat C, Rahman M, Lupton CE, Stewart J, Claridge-Chang A, Yen SC, Jesuthasan S. The right dorsal habenula limits attraction to an odor in zebrafish. Current Biology. 2014

Lahti L, Haugas M, Tikker L, Airavaara M, Voutilainen MH, Anttila J, Kumar S, Inkinen C, Salminen M, Partanen J. Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei. Development. 2016 Feb 1

Lima LB, Bueno D, Leite F, Souza S, Gonçalves L, Furigo IC, Donato J Jr, Metzger M. Afferent and efferent connections of the interpeduncular nucleus with special reference to circuits involving the habenula and raphe nuclei. J Comp Neurol. 2017 Jul 1

Machold R, Klein C, Fishell G. Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip. Gene Expr Patterns. 2011 Jun-Jul

Otsu Y, Lecca S, Pietrajtis K, Rousseau CV, Marcaggi P, Dugué GP, Mailhes-Hamon C, Mameli M, Diana MA. Functional Principles of Posterior Septal Inputs to the Medial Habenula. Cell Rep. 2018 Jan 16

Quina LA, Wang S, Ng L, Turner EE. Brn3a and Nurr1 mediate a gene regulatory pathway for habenula development. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 2009

Stephenson-Jones M, Floros O, Robertson B, Grillner S. Evolutionary conservation of the habenular nuclei and their circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. Proc Natl Acad Sci U S A. 2012 Jan 17

Tosches, Maria Antonietta, and Detlev Arendt. “The bilaterian forebrain: an evolutionary chimaera.” Current opinion in neurobiology 23.6 (2013): 1080-1089.

Zhang BB, Yao YY, Zhang HF, Kawakami K, Du JL. Left Habenula Mediates Light-Preference Behavior in Zebrafish via an Asymmetrical Visual Pathway. Neuron. 2017 Feb 22

Essay 19: Nucleus Isthmi

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On October 5, 2023

In Uncategorized

Essay 18 was trying to solve the problem of maintaining behavioral state. When a fast neuron synapse takes only 5ms, behavior that lasts seconds or minutes needs some circuit to sustain attention on the task. Essay 18 explored the striatum as a possible model to maintain behavior. In zebrafish, this problem is partial solved with a paired system consisting of the optic tectum (OT) and the nucleus isthmi (NI) [Gruberg et al. 2006].

Optic tectum

The optic tectum (OT – superior colliculus in mammals) is a midbrain action and sensor system that organizes vision, touch, sound, and action into retinotopic map like an air controller radar screen that activates only for important triggers. So, it’s not like the movie screen of primate vision, but is an action-oriented, sparse map that focuses on a few important items. In the larva zebrafish, the OT activates for hunting prey (paramecia) and avoiding obstacles and predators.

The OT itself has no persistence, When it detects potential prey and moves toward the prey, the OT doesn’t remember that it’s hunting or recall the previous location of the prey. Without enhancement, it forgets the pretend fails the hunt. The nucleus isthmi (NI – parabigeminal in mammals) provides that attention and persistence function [Henriques et al. 2019].

Nucleus isthmi circuit

The NI has a simple organization that is topologically, bidirectionally mapped to OT. The return signal from NI to OT is acetylcholine (ACh), which amplifies the sense input, biasing the next action to follow the previous action. Essentially this is a simple attention circuit that maintains consistent behavior.

Optic tectum and nucleus isthmi circuit as used in the essay 19 simulation.

In the diagram above, a left action sends an efference copy to the matching nucleus isthmi area, which can remember the activation for longer than the 5ms fast activation in the OT. In turn it sends an ACh modulator to amplify the left touch sensor, biasing the direction toward the same action.

For the essay simulation, the original problem was hitting an obstacle head-on, which triggered both left and right touch sensors, which then caused jitter as the animal randomly chose left and right without maintaining consistency. By adding an NI system, an initial left action would bias the left input sense to choose a next left action.

Acetylcholine attention system

As a speculation, or perhaps a mnemonic, this NI system where ACh enhances senses based on action might be a model for some attention mechanisms else were in the brain. NI is a sister nucleus to other ACh nuclei, specifically the parabrachial nucleus (B.pb) and the pedunculopontine nucleus (V.ppn), all developing from the same stem region near the isthmus. V.ppn is one of the major ACh attention nuclei and is part of the midbrain locomotive region (MLR). It seems plausible that V.ppn might share some organization with NI where its upstream ACh might support sense attention like the NI does for OT.

Engineering note

After implementing the nucleus isthmi support, both the proto-striatum and NI solve the jittering problem equally. The algorithms are slightly different — NI is a straight enhancement, while proto-striatum is a disinhibition with selection — but for the current complexity of the animal and environment, there’s no behavioral difference. Both proto-striatum and NI can be enabled simultaneously without interference problems.

References

Cui H, Malpeli JG. Activity in the parabigeminal nucleus during eye movements directed at moving and stationary targets. J Neurophysiol. 2003 Jun;89(6):3128-42. doi: 10.1152/jn.01067.2002. Epub 2003 Feb 26

Gruberg E., Dudkin E., Wang Y., Marín G., Salas C., Sentis E., Letelier J., Mpodozis J., Malpeli J., Cui H. Influencing and interpreting visual input: the role of a visual feedback system. J. Neurosci. 2006

Henriques PM, Rahman N, Jackson SE, Bianco IH. Nucleus Isthmi Is Required to Sustain Target Pursuit during Visually Guided Prey-Catching. Curr Biol. 2019 Jun 3

Marín G, Salas C, Sentis E, Rojas X, Letelier JC, Mpodozis J. A cholinergic gating mechanism controlled by competitive interactions in the optic tectum of the pigeon. J Neurosci. 2007 Jul 25

Motts SD, Slusarczyk AS, Sowick CS, Schofield BR. Distribution of cholinergic cells in guinea pig brainstem. Neuroscience. 2008 Jun 12;154(1):186-95. doi: 10.1016/j.neuroscience.2007.12.017. Epub 2008 Jan 28

18: Neuroscience issues with proto-striatum

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On October 3, 2023

In Uncategorized

The previous proto-striatum model is flawed because it focused too much on sensory input and not enough on action efferent copies. To fix this focus, the model can use midbrain locomotive region (MLR) actions as a bias selector.

Recall that the simulation needed the striatum to solve an action jitter problem by introducing a win-stay bias. Once the animal turns left, it should bias toward continued left turns. Before the fix, the animal randomly chose a direction every 50ms, reversing itself, causing problems in avoiding corners and obstacles. The simulation problem was an action-selection problem not a sensor problem.

In the vertebrate striatum, action feedback comes from the MLR via the parafascicular thalamus (T.pf). The T.pf connection to the striatum is unique, both in its targeting of striatal interneurons (S.cin and S.pv), but also for its connection to the medium spiny projection neurons (S.spn), the main striatal neurons [Ragu et al. 2006]. T.pf connects directly to S.spn dendrites, not merely the spines as with other inputs. This direct connection potentially gives a stronger stimulus, and its uniqueness suggests it may be an older, more primitive connection.

Action-focused striatum model

So, I’m changing the striatum model to follow an action focus. After an action fires the motor command neurons (B.rs reticulospinal), the MRL sends an efferent copy of the motor command to the striatum via T.pf.

Action feedback model for proto-striatum. B.rs reticulospinal motor command, MLR midbrain locomotive region, Ob olfactory bulb, Snc substantia nigra pars compacta, S.pv striatal parvalbumen interneuron, S.spn spiny projection neuron.

In the above diagram, the main sensor path is still from the olfactory bulb (Ob) to the substantia nigra pars compacta (Snc / posterior tuberculum) and then to MLR, basically a stimulus-response path. A previous action biases the sensory path for the next action by activating a corresponding S.spn, which disinhibits Snc, making the next sensory input more powerful.

Comparison with the previous model

As a comparison, the following diagram shows the previous striatal model. Unlike the new model, the final selected action didn’t bias the next action because there was no feedback connection. (The reset signal to S.pv is a different circuit, and doesn’t bias the decision because it applies to all choices equally.)

sense-focused proto-striatum model.
Previous photo-striatum, where a prior selected sense biased the next sense. B.ss somatosensory touch.

In addition, the sensory input must coordinate striatal disinhibition via S.spn with its excitation of the Snc action. Although not impossible evolutionarily, the double coordination required makes it less likely. The new model not only incorporates the action but simplifies the sensor circuit.

Parafascicular thalamus

For personal reference, here’s a summary of the T.pf connections [Smith et al. 2022].

Connections of the parafascicular thalamus.

Essentially all the T.pf inputs are motor efference copies and all the T.pf outputs are to the basal ganglia. Inputs include the following areas: vision/optic motor (OT and pretectum), midbrain locomotive region (MLR, M.pag, V.ppt, V.ldt), diencephalon locomotive region (H.zi), consummatory action (B.bp), forebrain attention (P.bf) and cortical action (C.fef, C.moss, C.gu). The cingulate cortex might be unusual (C.cc), although it also has motor areas.

Striatum as attention

Attention is a difficult topic, in part because it’s used in so many diverse ways that the word is often more confusing than helpful [Hommel et al. 2019], [Krauzlis et al. 2014]. However, I think it’s interesting that the action-based striatum model looks like selective attention.

Simplification of proto-striatum showing resemblance to selective attention.

When a left action biases the next action to stay the same, its mechanism is to enhance the sensory path, as if it’s paying attention more to one side than another.

Engineering feedback: dopamine mistake

When implementing this idea, the simulation doesn’t need dopamine feedback. Instead of forcing the dopamine just because the basal ganglia has dopamine feedback I’m taking it out from the model. Since I’ve only implemented a prototype portion of the basal ganglia, this may be okay instead of a fatal flaw. When the full model arises, we’ll see if this is a mistake.

Actual simulation implementation, removing dopamine and reset feedback.

Notice that the only dopamine in this model is descending, with no ascending dopamine [Ryczko and Dubuc 2017].

References

Hommel B, Chapman CS, Cisek P, Neyedli HF, Song JH, Welsh TN. No one knows what attention is. Atten Percept Psychophys. 2019 Oct

Krauzlis RJ, Bollimunta A, Arcizet F, Wang L. Attention as an effect not a cause. Trends Cogn Sci. 2014 Sep;18(9):457-64

Raju DV, Shah DJ, Wright TM, Hall RA, Smith Y. Differential synaptology of vGluT2-containing thalamostriatal afferents between the patch and matrix compartments in rats. J Comp Neurol. 2006 Nov 10

Ryczko D, Dubuc R. Dopamine and the Brainstem Locomotor Networks: From Lamprey to Human. Front Neurosci. 2017 May 26

Smith JB, Smith Y, Venance L, Watson GDR. Thalamic Interactions With the Basal Ganglia: Thalamostriatal System and Beyond. Front Syst Neurosci. 2022 Mar 25

18: Engineering issues with proto-striatum

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On October 1, 2023

In Uncategorized

The planned striatum model of essay 17 quickly runs into simulation problems because it’s missing priority selection between avoiding obstacles and seeking food. Obstacle avoidance needs a higher priority than seeking an odor plume, but a naive striatum doesn’t support that priority.

Broken striatum model where toward and away have no priority. Ob olfactory bulb, B.ss somatosensory touch, B.rs reticulospinal motor command.

This model fails because this striatum has no priority of away (avoid) actions from toward (approach) actions. An animal can’t simply follow an odor blindly, ignoring obstacles, but this model doesn’t support that priority.

Tectum

Adding the tectum seems like the right solution, although I was planning on putting it off until dealing with vision.

The tectum (optic tectum / superior colliculus) is better known for its vision support, but the deeper tectum layers are a general action-decision system. At its lower levels near periaqueductal gray (M.pag) it has a topographic direction-based map on its intermediate level and an action-based map in the deep level.

The tectum and M.pag are neighbors, almost layers of each other, and in animals like the frog, the M.pag is as a deeper layer of the tectum.

Relation between M.pag and OT in mammals (left) and frog (right), where the ventricle shape determines the anatomical label for homologous areas.

The tectum is an action organizer, not just a vision organizer. For the simulation, the action matters since the simulated animal doesn’t have vision.

Amphioxus, a non-vertebrate chordate that’s a model into pre-vertebrate evolution, has a few motor-related cells with the same genetic markers as the tectum [Pergner et al. 2020]. It’s conceivable that the amphioxus tectum is more action focused, since the amphioxus frontal eye is only a dozen photoreceptors with no lens.

Action categories

The tectum has split circuits for turning and for approach and avoid [Wheatcroft et al. 2022]. The simulation can use something like the following circuit.

Split tectum and striatum circuit. B.rs reticulospinal motor command, B.ss somatosensory input, M.lr midbrain locomotor region, M.pag periaqueductal gray, Ob olfactory bulb, S.d dorsal striatum, S.ot olfactory tubercle.

Approach (toward) senses like food odors excited toward actions, and avoidant (away) sense like touch excite away actions. Because the priority areas are split, each striatum can choose between non-priority options (left vs right). The priority resolves only later in the midbrain locomotor region, using context input to decide which major direction to use. In this split model, the simplified striatum circuit can work because all of striatum options are equal priority.

As a note on accuracy, the diagram misrepresents the actual olfactory path, specifically the real olfactory tubercle. In reality, olfaction has a distant, complicated path to the tectum.

Short-cut escape signal

The previous diagram is also misleading because it’s too organized, as if each function has a dedicated, planned circuit. Although the tectum itself is highly-organized, the downstream and modulating circuits are more ad hoc. For example, the zebrafish has an escape mechanism that short-cuts the tectum and drives the B.rs command motor directly [Zwaka et al. 2022].

fast escape shortcut of tectal locomotion circuit.
Fast escape shortcut of tectum-mediated locomotion.

In the above diagram, the escape circuit short-circuits any decisions of the tectum and striatum. Relatedly, the “switch” area in M.lr isn’t as tidy as the diagram suggests. It’s more like that M.lr contains multiple actions which laterally inhibit each other in a priority scheme, modulated by M.pag.

As an additional correct, many of the modulators like M.pag affect the tectum directly, instead of the diagram’s dedicated priority-resolution function.

References

Pergner J, Vavrova A, Kozmikova I, Kozmik Z. Molecular Fingerprint of Amphioxus Frontal Eye Illuminates the Evolution of Homologous Cell Types in the Chordate Retina. Front Cell Dev Biol. 2020 Aug 4

Wheatcroft T, Saleem AB, Solomon SG. Functional Organisation of the Mouse Superior Colliculus. Front Neural Circuits. 2022 Apr 29

Zwaka H, McGinnis OJ, Pflitsch P, Prabha S, Mansinghka V, Engert F, Bolton AD. Visual object detection biases escape trajectories following acoustic startle in larval zebrafish. Curr Biol. 2022 Dec 5

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