Attempting a toy model of vertebrate understanding

Month: June 2024

Essay 33: Klinotaxis

When seeking an odor, vertebrate swimming undulates left and right, naturally moving the nose perpendicular to the body motion. This lateral motion can help navigation if odor sampling can be coordinated with the movement, enabling a spatiotemporal gradient calculation along the path of the nose movement. This lateral sampling over time is called klinotaxis (“leaning navigation”) or weathervaning.

Essay 24 and essay 25 explored head-direction navigation as inspired by the fruit fly Drosophila fan-shaped body and ellipsoid body. The idea was to use head direction to translate egocentric movement into an allocentric memory of past samples, independent of the current body direction. In contrast, klinotaxis uses an egocentric system, where the lateral motion is relative to the current direction, not an independent, compass or map-like system.

Klinotaxis in Drosophila larva and C. elegans

Klinotaxis has been largely studied in the fruit fly Drosophila larva and the roundworm C. elegans. Drosophila larva have a distinct “cast” movement, where they pause and wave their heads side to side, either a single time (1-cast) or multiple times (n-cast) [Zhao et al 2017]. Larva movements break down into five major types [Gomez-Marin and Louis 2014]:

  • Forward
  • Backward
  • Stop
  • Turn
  • Cast

C. elegans has two major seek movements: pirouettes and weathervaning [Lockery 2011]. Pirouettes are a u-turn when the animal is moving away from the odor. Weathervaning is a side-to-side head movement that manages turning.

Both systems are temporal gradient systems, requiring measurements at different times and a memory of the older measurement [Chen X and Engert 2014]. Klinotaxis requires a basic form of memory [Karpenko et al 2020], but the comparison can be a simple ON or OFF result [Lockery 2011]. Pirouetts use a gradient parallel to body motion and reverse direction when the animal is moving away from the odor [Iino and Yoshida 2009]. Weathervaning uses a gradient perpendicular to body motion, measured with a lateral head movement [Lockery 2011].

This klinotaxis contrasts with a bilateral spatial navigation that compares two lateral sensors [Chen X and Engert 2014], such as bilateral eyes, ears, or nostrils. In Drosophila larva, odor turning is proportional to the lateral gradient more than the parallel gradient [Martinez 2014]. The odor navigation is not simply bilateral because disabling one side of O.sn (olfactory sensory neuron) only minimally impairs navigation [Gomez-Marin and Louis 2014].

As a slight digression, let’s return to the adult Drosophila navigation, because the structure can be a useful analogy for understanding vertebrate klinotaxis navigation, despite using a different allocentric system.

Adult Drosophila FSB

Below is a rough sketch of the Drosophila navigation circuit, focused on the fan-shaped body [Hulse et al 2021]. The ellipsoid body (EB) and protocerebral bridge (PB) calculate head direction and sort it into 18 columns. This head direction is allocentric, independent of the animal’s current direction, like a compass direction or a map. Input from odor areas like the mushroom body (MB) and lateral horn (LN) are organized into 9 rows. The fan-shaped body combines these 18 head direction columns and 9 sense data rows into a memory table.

Drosophila navigation
Drosophila navigation, focusing on head direction from PB, odor data from MB and LH, and allocentric table of FB. EB ellipsoid body, FB fan-shaped body, LH lateral horn, MB mushroom body.

Motor navigation reads out from the fan-shaped-body table. These motor commands include left and right, but also include a separate u-turn command [Westeinde et al. 2022]. Although this allocentric navigation system differs from egocentric klinotaxis, its motor output includes both the left vs right from weathervaning and the u-turn from pirouette.

The previous essay 24 and essay 25 attempts followed this model. As the animal moves in space, the model saved the forward odor gradient according to the current head direction. By comparing stored values for other head directions, the animal would improve its heading toward the direction with the strongest odor.

The fan-shaped body then becomes a record of samples of all the older directions that the animal had measured. Output is then calculated for left (PFL3L), right (PFL3R), and u-turn (PFL2) signals. [Westeinde et al 2024]. The current head direction is represented as a sinusoidal neural pattern and combined with the stored values to produce an output.

This system was only partially successful for the essay. Although it was an improvement over no memory, because the animal was continually moving in space, the table was always obsolete. Even when the table memory times out to represent loss in accuracy as the animal moves, the rapid obsolescence made navigation difficult, particularly as the animal neared the target.

So, this essay simplifies the circuit and lowers the ambition. Instead of trying to record every direction and keeping perfect allocentric compass direction, the animal could simple save its left and right oscillation as it swims naturally.

Vertebrate Hb.m and R.ip

The vertebrate Hb.m (medial habenula) to R.ip (interpeduncular nucleus) is used for phototaxis [Chen X and Engert 2014], Chemotaxis [Chen WY et al 2019] and thermotaxis [Palieri et al 2024]. In a clever experiment creating a virtual light circle, Chen and Engert shows that the zebrafish phototaxis is not simply comparing light between the eyes for a spatial gradient (tropotaxis) but is a temporally-based gradient (klinotaxis), relying on a short term memory of the previous light. This phototaxis uses the Hb.m to R.ip circuit [Chen X and Engert 2014].

Vertebrate olfactory klinotaxis circuit. Ob (olfactory bulb), Hb.m (medial habenula), P.ldt (laterodorsal tegmental nucleus), R.dtg (dorsal tegmental nucleus of Gudden), R.ip (interpeduncular nucleus), R.rs (reticulospinal), V.mr (median raphe)

Head direction from R.dgt (dorsal tegmental nucleus) tiles R.ip vertically [Petrucco et al 2023], while olfactory and light input is organized horizontally [Chen WY et al 2019], [Zaupa et al 2021]. After combining the odor with the head direction and comparing with the stored values, it sends motor commands to R.rs (reticulospinal) using P.ldt (laterodorsal tegmental nucleus) and V.mr (median raphe). The vertebrate R.ip has 6 columns of head direction input from R.dtg, resembling the Drosophila fan-shaped body, but instead of 18 columns for the fan-shaped body, R.ip only has 6, three to a side [Petrucco et al 2023].

Essay 25 explored a model which used the Drosophila fan-shaped body allocentric navigation in R.ip with some limited but not overwhelming success. Instead, this essay will try a different interpretation, where R.ip is only storing side to side weathervaning of the head while swimming, instead of a full 360 degree table like Drosophila.

Vertebrate klinotaxis

As a different approach, suppose the head direction to R.ip is not an allocentric map-making coordinator as in the adult Drosophila, but a simpler egocentric weathervaning or casting coordinator, storing only the lateral gradient from head direction changes from natural swimming, or possibly deliberate larger turns like casting to gather wider lateral gradient information.

Klinotaxis simplifies the need for precise head direction. Instead of the Drosophila 18 head direction columns calibrated to the outside world, we use only three, two lateral and one central, that only require motor efference copies of left and right muscle turns. Studies from the zebrafish R.ip suggest three columns to a side, which isn’t connected to the vestibular system [Petrucco et al 2023]. To me, this suggests to me that the head direction might not be an allocentric signal that requires precise direction, but a simple egocentric lateral measurement, which doesn’t need vestibular information.

Vertebrate thigmotaxis circuit. Hb.m (medial habenula), Ob (olfactory bulb), R.dtg (dorsal tegmental nucleus), R.ip (interpeduncular nucleus).

The above diagram illustrates the system. Olfactory samples arrive through Hb.mand head direction arrives from R.dtg. Like the Drosophila fan-shaped body, R.ip combines odor samples with lateral head movement into a simple memory table, and it reads out left and right motor commands. A similar system can save odor measurements parallel to body movement, using velocity instead of head direction, to trigger a u-turn when the animal is moving away from the odor.

Discussion

Compared to the parallel-only gradient, allocentric system of essay 25, this lateral navigation is far simpler and more effective. Even with only three bins compared to the 8 bins in essay 25, the lateral weathervaning turned out to be more effective and less brittle. If R.ip does implement a lateral klinotaxis system like this essay, it’s plausible that the 6 directions reported by [Westeinde et al 2024] are sufficient for accurate seek navigation. In contract, those 6 directions seem insufficient for an allocentric navigation compared to the Drosophila 18 directions.

Interestingly, the pirouette also highly effective, even without lateral klinotaxis. In the simulation, when the animal moved away from the odor source, it makes a u-turn. This system served to ratchet the animal closer and closer to the target. Even when most of the movement was random, the pirouette locks in any improvement. Pirouette itself is also simple, only requiring two averages: a short average and a long average, where a short average tracks the odor across a single swim cycle and a long average uses two swim cycles. When the short average has a stronger odor value than the long average, the animal is moving toward the odor.

In both cases, the simulation used a binary OFF for the motor command instead of attempting finer precision from the gradient. This simple OFF strategy was sufficient for the simulation. A C. elegans study suggested that ON-OFF coding was energy efficient, and the worm rarely orients perfectly to the gradient [Lockery 2011].

References

Chen WY, Peng XL, Deng QS, Chen MJ, Du JL, Zhang BB. Role of Olfactorily Responsive Neurons in the Right Dorsal Habenula-Ventral Interpeduncular Nucleus Pathway in Food-Seeking Behaviors of Larval Zebrafish. Neuroscience. 2019 Apr 15;404:259-267. 

Chen X, Engert F. Navigational strategies underlying phototaxis in larval zebrafish. Front Syst Neurosci. 2014 Mar 25;8:39.

Gomez-Marin A., Louis M. (2014). Multilevel control of run orientation in Drosophila larval chemotaxis. Front. Behav. Neurosci. 8:38 10.3389/fnbeh.2014.00038.

Hulse, B. K., Haberkern, H., Franconville, R., Turner-Evans, D., Takemura, S. Y., Wolff, T., … & Jayaraman, V. (2021). A connectome of the Drosophila central complex reveals network motifs suitable for flexible navigation and context-dependent action selection. Elife, 10.

Iino Y, Yoshida K. Parallel use of two behavioral mechanisms for chemotaxis in Caenorhabditis elegans. J Neurosci. 2009 Apr 29;29(17):5370-80. 

Karpenko S, Wolf S, Lafaye J, Le Goc G, Panier T, Bormuth V, Candelier R, Debrégeas G. From behavior to circuit modeling of light-seeking navigation in zebrafish larvae. Elife. 2020 Jan 2;9:e52882. 

Lockery SR. The computational worm: spatial orientation and its neuronal basis in C. elegans. Curr Opin Neurobiol. 2011 Oct;21(5):782-90. 

Martinez D. Klinotaxis as a basic form of navigation. Front Behav Neurosci. 2014 Aug 14;8:275. 

Palieri V, Paoli E, Wu YK, Haesemeyer M, Grunwald Kadow IC, Portugues R. The preoptic area and dorsal habenula jointly support homeostatic navigation in larval zebrafish. Curr Biol. 2024 Feb 5;34(3):489-504.e7.

Petrucco L, Lavian H, Wu YK, Svara F, Štih V, Portugues R. Neural dynamics and architecture of the heading direction circuit in zebrafish. Nat Neurosci. 2023 May;26(5):765-773. 

Westeinde EA, Kellogg E, Dawson PM, Lu J, Hamburg L, Midler B, Druckmann S, Wilson RI. Transforming a head direction signal into a goal-oriented steering command. Nature. 2024 Feb;626(8000):819-826. 

Zaupa M, Naini SMA, Younes MA, Bullier E, Duboué ER, Le Corronc H, Soula H, Wolf S, Candelier R, Legendre P, Halpern ME, Mangin JM, Hong E. Trans-inhibition of axon terminals underlies competition in the habenulo-interpeduncular pathway. Curr Biol. 2021 Nov 8;31(21):4762-4772.e5. 

Zhao W, Gong C, Ouyang Z, Wang P, Wang J, Zhou P, Zheng N, Gong Z. Turns with multiple and single head cast mediate Drosophila larval light avoidance. PLoS One. 2017 Jul 11;12(7):e0181193. 

Essay 32: Indirect search

The ascidian circuit in essay 30 had an interesting dopamine subcircuit that looks like an indirect search, where the ascidian coronet cells modulate the underlying phototaxis and geotaxis circuits. While the function of the coronet cells is unknown, if these cells are another seeking system like following an odor, then the coronet sub circuit follows odor by modulating different seek circuits: phototaxis and geotaxis.

Ascidian analogy

Tunicates are the closest non-vertebrate chordates evolutionarily, but they have developed in vastly different directions from the vertebrates, and likely very differently from the shared common ancestor [Holland 2015]. The ascidian tunicates, which are the most studied tunicates, live their asul life as sessile filter feeders like sponges. Their eggs hatch in only 20 hours and their brief tadpole form lasts only for a few hours, just enough to swim and disperse to find a likely permanent settlement place. Their locomotive strategy is to swim up using geotaxis in the morning and swim down using phototaxis in the afternoon. If they’re lucky enough to find a ledge, they swim up into the ledge’s shadow to settle because hanging like a bat from a ledge offers more protection from some predators than resting on the ocean floor [Zega et al 2006].

As would be expected from a 20-hour brain, the navigation circuit is fairly simple. There are two distinct action paths, one for geotaxis using a heavy pigment cell and one for phototaxis using photoreceptors and another pigment cell as a shadow to provide photo-directionality. The two action paths are connected, where dimming produces upward swimming [Bostwick et al 2020].

Ascidian tadpole sub circuit for geotaxis and phototaxis. The horizontal neurons are the main action paths. The coronet DA cells modulate the action paths.

In the above diagram, the geotaxis action path starts from the otolith (“ear stone”) receptor ant2, which is functionally similar to the vestibular system (but not related), passes input to antenna relay neurons (antRN) and then to the right side motor neurons (mgIN-R and MN-r) [Ryan et al 2016]. Similarly, the phototaxis action path starts from the ocellus (eyespot) to the phototaxis relay (prRN) and to the left motor neurons, providing an opposing direction from geotaxis. Importantly for the following discussion, each path has a weak connection to the opposite direction, possibly to add some stochasticity to the movement to improve dispersion of the many tadpoles.

The function of the coronet cells is unknown, although they have some genetic connection the palp sensory cells [Cao et al 2019]. Other papers compare the corona cells to dopamine cells in the hypothalamus and Ob (olfactory bulb) [Horie et al 2018] or ancestral photo-hypothalamus and retina [Sharma et al 2019], possibly related to the fish saccus vasculosus area of the hypothalamus, responsible for some circadian behavior. However, the ascidian tadpole has lost circadian clock genes, which argues against circadian timing [Chung et al 2023]. The coronet cells can accumulate serotonin and the DA might promote onset of metamorphosis [Razy-Kraika et al 2012]. So, the coronet may be involved in triggering metamorphic changes at twilight, which causes the tadpole to dive to deeper waters [Lemaire et al 2021].

Whatever the source, the interesting thing about the circuit is that it’s an indirect modulation of underlying taxis action paths. The action of the coronet is gating or modulatory. While this coronet circuit is not homologous to the basal ganglia, using it as an analogy may be useful. For example, dopamine is a sleep / wake signal for the basal ganglia [Vetrivelan et al 2010]. Because low dopamine reduces basal ganglia activity both at the striatum input layer and the Snr (substantia nigra pars reticulata) output layer, it’s an effective sleep controller.

Indirect chemotaxis

Consider indirect chemotaxis, where the animal is seeking toward the odor, but the underlying action path is phototaxis or geotaxis, like the ascidian circuit above. If the animal detects an odor, it increases the current direction. In other words, the current direction is toward or near a food odor. This strategy is like the e. coli tumble-and-run strategy, where the bacteria runs further when the odor gradient is increasing.

Consider the basal ganglia as an analogy. For example, Ob has some dopamine interneurons (Ob.sac – short axis cells) that project to S.ot (olfactory tubercle) [Burton 2017], a portion of the stratum focused on olfactory input. For the corollary of the phototaxis path, consider the Hb.m (medial habenula) phototaxis path [Zhang et al 2017].

Hypothetical indirect seek circuit where chemotaxis uses an underlying phototaxis to hunt for food. Hb (habenula), Ob (olfactory bulb), P (pallidum), R.ip (interpeduncular nucleus), R.rs (reticulospinal motor neurons), S (striatum), V.mr (median raphe).

When the odor is detected, Ob enables the basal ganglia, which enhances the phototaxis path. If the odor isn’t detected, the default semi-suppressed behavior means the direction is semi-random. This indirect control would allow for seeking odor when the underlying navigation is phototaxis and geotaxis.

Discussion

After writing this description. I think this model may be a bit sketch for something like chemotaxis, although it’s a reasonable model for sleep. Because I’m not sure the idea is likely to be productive, I’m holding off on doing any implementation, but writing down the description in case it makes sense later.

References

Bostwick M, Smith EL, Borba C, Newman-Smith E, Guleria I, Kourakis MJ, Smith WC. Antagonistic Inhibitory Circuits Integrate Visual and Gravitactic Behaviors. Curr Biol. 2020 Feb 24;30(4):600-609.e2. 

Burton SD. Inhibitory circuits of the mammalian main olfactory bulb. J Neurophysiol. 2017 Oct 1;118(4):2034-2051.

Cao C, Lemaire LA, Wang W, Yoon PH, Choi YA, Parsons LR, Matese JC, Wang W, Levine M, Chen K. Comprehensive single-cell transcriptome lineages of a proto-vertebrate. Nature. 2019 Jul;571(7765):349-354. 

Chung J, Newman-Smith E, Kourakis MJ, Miao Y, Borba C, Medina J, Laurent T, Gallean B, Faure E, Smith WC. A single oscillating proto-hypothalamic neuron gates taxis behavior in the primitive chordate Ciona. Curr Biol. 2023 Aug 21;33(16):3360-3370.e4.

Holland, L. Z. (2015). Genomics, evolution and development of amphioxus and tunicates: the Goldilocks principle. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution, 324(4), 342-352.

Horie T, Horie R, Chen K, Cao C, Nakagawa M, Kusakabe TG, Satoh N, Sasakura Y, Levine M. Regulatory cocktail for dopaminergic neurons in a protovertebrate identified by whole-embryo single-cell transcriptomics. Genes Dev. 2018 Oct 1;32(19-20):1297-1302. 

Lemaire LA, Cao C, Yoon PH, Long J, Levine M. The hypothalamus predates the origin of vertebrates. Sci Adv. 2021 Apr 28;7(18):eabf7452. 

Razy-Krajka F, Brown ER, Horie T, Callebert J, Sasakura Y, Joly JS, Kusakabe TG, Vernier P. Monoaminergic modulation of photoreception in ascidian: evidence for a proto-hypothalamo-retinal territory. BMC Biol. 2012 May 29;10:45. 

Ryan K, Lu Z, Meinertzhagen IA. The CNS connectome of a tadpole larva of Ciona intestinalis (L.) highlights sidedness in the brain of a chordate sibling. Elife. 2016 Dec 6;5:e16962. 

Sharma S, Wang W, Stolfi A. Single-cell transcriptome profiling of the Ciona larval brain. Dev Biol. 2019 Apr 15;448(2):226-236. 

Vetrivelan R, Qiu MH, Chang C, Lu J. Role of Basal Ganglia in sleep-wake regulation: neural circuitry and clinical significance. Front Neuroanat. 2010 Nov 23;4:145. 

Zega, G., Thorndyke, M. C., & Brown, E. R. (2006). Development of swimming behaviour in the larva of the ascidian Ciona intestinalis. Journal of experimental biology, 209(17), 3405-3412.

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;93:914–28.

Essay 31: Striatum as Timeout

Let’s return to the task of essay 16 on give-up time in foraging, which covered food search with a timeout. At first the animal uses a general roaming search and if it smells a food odor, it switches to a targeted seek following the odor with chemotaxis. If the animal finds food in the odor plume, it eats the food, but if it doesn’t find food, it will eventually give up and avoid the local area before returning to the roaming search.

Search state machine. Roam is the starting state, switching to seek when it detects odor, and switching to avoid after a timeout.

For another attempt at the problem, let’s take the striatum (basal ganglia) as implementing the timeout portion of this task using the neurotransmitter adenosine as a timeout signal and incorporating the multiple action path discussion from essay 30 on RTPA. Adenosine is a byproduct of ATP breakdown and is a measure of cellular activity. With sufficiently high adenosine, the striatum switches from the active seek path to an avoidance path. These circuits are where caffeine works to suppress the adenosine timeout, allowing for longer concentration.

Mollusk navigation

As mentioned in essay 30, the mollusk sea slug has a food search circuit with a similar logic to what we need here. The animal seeks food odors when it’s hungry, but it avoids food odors when it’s not hungry [Gillette and Brown 2015].

Mollusk food search circuit, modulated by hunger.
Mollusk food search circuit, illustrating a hunger-modulated switchboard. When the animal is not hungry, the switchboard reverses the odor to motor links turning it away from food.

This essay uses the same idea but replaces the hunger modulation with a timeout. When the timeout occurs, the circuit switches from a food seek action path to a food avoid action path.

Odor action paths

Two odor-following actions paths exist in the lamprey, one using Hb.m (medial habenula) and one using V.pt (posterior tuberculum). The Hb.m path is a chemotaxis path following a temporal gradient. The V.pt path projects to MLR (midbrain locomotor region), but The lamprey Ob.m (medial olfactory bulb) projects to both Hb.m (medial habenula) and to V.pt (posterior tuberculum), which each project to different locomotor paths [Derjean et all 2010], Hb.m to R.ip (interpeduncular nucleus) and V.pt to MLR (midbrain locomotor region). The zebrafish also has Ob projections to Hb and V.pt [Imamura et al 2020], [Kermen et al 2013].

Dual odor-seeking action paths in the lamprey and zebrafish. Hb (habenula), Ob.m (medial olfactory bulb), V.pt (posterior tectum).

Further complicating the paths, the Hb.m itself contains both an odor seeking path and an odor avoiding path [Beretta et al 2012], [Chen et al 2019]. Similarly Hb.m has dual action paths for social winning and losing [Okamoto et al 2021]. So, this essay could use the dual paths in Ob.m instead of contrasting Ob.m with V.pt, but the larger contract should make the simulation easier to follow.

This essay’s simulation makes some important simplifications. The Hb to R.ip path is a temporal gradient path used for chemotaxis, phototaxis and thermotaxis. In a real-world marine environment, odor diffusion and water turbulence is much more complicated, producing more clumps and making a simple gradient ascent more difficult [Hengenius et al 2012]. Because this essay is only focused on the switchboard effect, this simplification should be fine.

Striatum action paths with adenosine timeout

The timeout circuit uses the striatum, which has two paths: one selecting the main action, and the second either stopping the action, or selecting an opposing action [Zhai et al 2023]. The two paths are distinguished by their responsiveness to dopamine with S.d1 (striatal projection with D1 G-s stimulating) or S.d2 (striatal projection with D2 G-i inhibiting) marking the active and alternate paths respectively. This model is a simplification of the mammalian striatum where the two paths interact in a more complicated fashion [Cui et al 2013].

Essay odor seek with timeout circuit. The seek path flows from Ob, through S.d1 to P.v to V.pt. The avoid path flows from Obj, though S.d2 to Pv. to Hb. Ad (adenosine), Hb (habenula), Ob (olfactory bulb), Pv (ventral pallidum), S.d1 (striatum D1 projection neuron), S.d2 (striatum D2 projection neuron), V.pt (posterior tuberculum)

As mentioned, the two actions paths are the seek path from Ob to V.pt and the avoid path from Ob to Hb. For the timeout and switchboard, the Ob has a secondary projection to the striatum. Although this circuit is meant as a proto-vertebrate simplification, Ob does project to S.ot (olfactory tubercle) and to the equivalent in zebrafish [Kermen et al 2013].

The timeout is managed by adenosine, which is a neurotransmitter derived from ATP and a measure of neural activity. The striatum has three sub-circuits for this kind of functionality, which I’ll cover in order of complexity.

S.d1 and adenosine inhibition

The first circuit only uses the direct S.d1 path and adenosine as a timeout mechanism. When the animal follows an odor, the Ob to S.d1 signal enables the seek action. As a timeout, ATP from neural activity degrades to adenosine and the buildup of adenosine is a decent measure of activity over time. The longer the animal seeks, the more adenosine builds up. Of the Ob projection axis contains an A1i (adenosine G-i inhibitory) receptor, the adenosine will inhibit the release of glutamate from Ob, which will eventually self-disable the seek action.

S.d1 action path inhibited by adenosine buildup as a timeout. A1i (adenosine G-i inhibitory receptor), Ad (adenosine), mGlu5q (metabotropic glutamate G-q receptor), Ob (olfactory bulb), S.d1 (D1-type striatal projection neuron)

In practice, the striatum uses astrocytes to manage the glutamate release. An astrocyte that envelops the synapse measures glutamate release with an mGlu5q (metabotropic glutamate with G-q/11 binding) receptor and accumulates internal calcium [Cavaccini et al 2020]. The astrocyte’s calcium triggers an adenosine release as a gliotransmitter, making the adenosine level a timeout measure of glutamate activity. The presynaptic A1i receptor then inhibits the Ob signal. The timeframe is on the order of 5 to 20 minutes with a recovery of about 60 minutes, although the precise timing is probably variable. Interestingly, the time-out is a log function instead of linear measure of activity [Ma et al 2022].

This circuit doesn’t depend on the postsynaptic S.d1 firing [Cavaccini et al 2020], which contrasts with the next LTD (long term depression) circuit which only inhibits the axon if the S.d1 projection neuron fires.

S.d1 presynaptic LTD using eCB

S.d1 self-activating LTD uses retrotransmission to inhibit its own input using eCB (endocannabiniods) as a neurotransmitter. Like the astrocyte in the previous circuit, S.d1 uses a mGlu5q receptor to trigger eCB release, but also require that S.d1 fire, as triggered by NMDA glutamate receptor. The axon receives the eCB retrotransmission with a CB1i (cannabinoid G-i inhibitory) receptor and trigger presynaptic LTD [Shen et al 2008], [Wu et al 2015]. Like the previous circuit, the timeframe seems to be on the order of 10 minutes, lasting for 30 to 60 minutes.

S.d1 LTD circuit. A coincidence of glutamate detection with mGlu5q and S.d1 activation with NMDA triggers eCB release, which activates CB1i leading to presynaptic LTD. CB1i (cannabinoid G-i inhibitory receptor), mGlu5q (glutamate G-q receptor), Ob (olfactory bulb), S.d1 (striatum D1-type projection neuron).

This circuit inhibits itself over time without using adenosine or astrocytes. In the full striatum circuit, high dopamine levels suppress this LTD suppression, meaning that dopamine inhibits the timeout [Shen et al 2008].

The next circuit adds the S.d2 path, which uses adenosine and self-activity to trigger postsynaptic LTD.

S.d2 postsynaptic LTP via A2a.s

Consider a third circuit that has the benefits of both previous circuits because it uses adenosine as a timer managed by astrocytes and is also specific to postsynaptic activity. In addition, it allows for a second action path, changing the circuit from a Go/NoGo system to a Go/Avoid action pair. This circuit uses LTP (long term potentiation) on the S.d2 striatum neurons.

Timeout circuit using postsynaptic LTD at the S.d2 neuron and adenosine as a timeout signal. As adenosine accumulates, it stimulates S.d2, which both disables S.d1 and drives the avoid path. A2a.s (adenosine G-s stimulatory receptor), Ad (adenosine), mGlu5q (glutamate G-q metabotropic receptor), Ob (olfactory bulb), S.d1 (striatum D1-type projection neuron), S.d2 (striatum D2-type projection neuron)

When the odor first arrives, Ob activates the S.d1 path, seeking toward the odor. S.d1 is activated instead of S.d2 because of dopamine. In this simple model, the Ob itself could provide the initial dopamine like c. elegans odor-detecting neurons or the tunicate’s coronal cells or the dual glutamate and dopamine neurons in Vta (ventral tegmental area).

As time goes on, adenosine from the astrocyte builds up, which activates the S.d2 A2s.a (adenosine G-s stimulatory receptor) until it overcomes dopamine suppression and increases the S.d2 activity with LTP [Shen et al 2008]. Once S.d2 activates, it suppresses S.d1 [Chen et al 2023] and drives the avoid path.

The combination of these circuits looks like it’s precisely what the essay needs.

Simulation

In the simulation, when the animal is hunting food and finds a food odor plume, it directly seeks toward the center and eats if it find food. In the screenshot below, the animal is eating.

Simulation showing the animal eating food after seeking the odor plume.

Satiation disables the food seek. This might sound obvious, but hunger gating of food seeking requires specific satiety circuits to any seek path that’s food specific, which means the involvement of H.l (lateral hypothalamus) and related areas like H.arc (arcuate hypothalamus) and H.pv (periventricular hypothalamus). And, of course, the simulation requires simulation code to only enable food odor seek when the animal is searching for food.

The next screenshot shows the central problem of the essay, when the animal seeks a food odor but there’s no food at the center.

Screenshot showing the animal stuck in the middle of the food odor plume before the timeout.

Without a timeout, the animal circles the center of the food odor plume endlessly. After a timeout, the animal actively leaves the plume and avoid that specific odor until the timeout decays.

Screenshot showing the animal escaping from the odor plume after the timeout.

This system is somewhat complex because of the need for hysteresis. A too-simple solution with a single threshold can oscillate, because as soon as the animal starts leaving the timeout decays, which then re-enables the food-seek, which then quickly times out, repeating. Instead, the system needs to make re-enabling of the food seek more difficult after a timeout.

But that adds a secondary issue because if food seek is a lower threshold, then the sustain of seek needs to raise the threshold while the seek occurs. So, the sustain of seek needs a lower threshold than starting seek. This hysteresis and seek sustain presumably needs to be handled by the actual striatum circuit.

Discussion

I think this essay shows that using the stratum for an action timeout for food seek is a plausible application. The circuit is relatively simple and is effective, improving search by avoiding failed areas.

However, the simulation does raise some issues, particularly hysteresis problem. If the striatum does provide a timeout along these lines, it must somehow solve the hysteresis problem. While the animal is seeking, the ongoing LTP/LTD inhibition should use a high threshold to stop seeking, but once avoidance starts, there needs to be a high threshold to return to seeking to avoid oscillations between the two action paths.

Because LTD/LTP is a relatively long chemical process (minutes) internal to the neurons, as opposed to an instant switch in the simulation, the delay itself might be sufficient to solve the oscillation problem. It’s also possible that some of the more complicated parts of the circuit, such as P.ge (globus pallidus) and its feedback to the striatum or H.stn (subthalamic nucleus) might affect the sustain of seek or breaking it and so control the hysteresis problem.

The simulation also reinforced the absolute requirement that action paths need to be modulated by internal state like hunger. For the seek paths, both Hb.m and V.pt are heavily modulated by H.l and other hypothalamic hunger and satiety signals.

As expected, the simulation also illustrated the need for context information separate from the target odor. While the food odor is timed out, the animal can’t search the other odor plume because this essay’s animal can’t distinguish between the odor plumes, and therefore avoids both odors. With a long timeout and many odor plumes, this delays the food search. A future enhancement is to add context to the timeout. If the animal can timeout a specific odor plume, it can search alternatives even if the food odor itself is identical.

References

Beretta CA, Dross N, Guiterrez-Triana JA, Ryu S, Carl M. Habenula circuit development: past, present, and future. Front Neurosci. 2012 Apr 23;6:51. 

Cavaccini A, Durkee C, Kofuji P, Tonini R, Araque A. Astrocyte Signaling Gates Long-Term Depression at Corticostriatal Synapses of the Direct Pathway. J Neurosci. 2020 Jul 22;40(30):5757-5768. 

Chen JF, Choi DS, Cunha RA. Striatopallidal adenosine A2A receptor modulation of goal-directed behavior: Homeostatic control with cognitive flexibility. Neuropharmacology. 2023 Mar 15;226:109421. 

Chen WY, Peng XL, Deng QS, Chen MJ, Du JL, Zhang BB. Role of Olfactorily Responsive Neurons in the Right Dorsal Habenula-Ventral Interpeduncular Nucleus Pathway in Food-Seeking Behaviors of Larval Zebrafish. Neuroscience. 2019 Apr 15;404:259-267. 

Cui G, Jun SB, Jin X, Pham MD, Vogel SS, Lovinger DM, Costa RM. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature. 2013 Feb 14;494(7436):238-42.

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;8(12):e1000567. 

Gillette R, Brown JW. The Sea Slug, Pleurobranchaea californica: A Signpost Species in the Evolution of Complex Nervous Systems and Behavior. Integr Comp Biol. 2015 Dec;55(6):1058-69. 

Hengenius JB, Connor EG, Crimaldi JP, Urban NN, Ermentrout GB. Olfactory navigation in the real world: Simple local search strategies for turbulent environments. J Theor Biol. 2021 May 7;516:110607.

Imamura F, Ito A, LaFever BJ. Subpopulations of Projection Neurons in the Olfactory Bulb. Front Neural Circuits. 2020 Aug 28;14:561822. 

Kermen F, Franco LM, Wyatt C, Yaksi E. Neural circuits mediating olfactory-driven behavior in fish. Front Neural Circuits. 2013 Apr 11;7:62.

Ma L, Day-Cooney J, Benavides OJ, Muniak MA, Qin M, Ding JB, Mao T, Zhong H. Locomotion activates PKA through dopamine and adenosine in striatal neurons. Nature. 2022 Nov;611(7937):762-768.

Okamoto H, Cherng BW, Nakajo H, Chou MY, Kinoshita M. Habenula as the experience-dependent controlling switchboard of behavior and attention in social conflict and learning. Curr Opin Neurobiol. 2021 Jun;68:36-43. 

Shen W, Flajolet M, Greengard P, Surmeier DJ. Dichotomous dopaminergic control of striatal synaptic plasticity. Science. 2008 Aug 8;321(5890):848-51. 

Wu YW, Kim JI, Tawfik VL, Lalchandani RR, Scherrer G, Ding JB. Input- and cell-type-specific endocannabinoid-dependent LTD in the striatum. Cell Rep. 2015 Jan 6;10(1):75-87. 

Zhai S, Cui Q, Simmons DV, Surmeier DJ. Distributed dopaminergic signaling in the basal ganglia and its relationship to motor disability in Parkinson’s disease. Curr Opin Neurobiol. 2023 Dec;83:102798.

Powered by WordPress & Theme by Anders Norén