Can a Shot in the Foot Help Depression? Neuroscientists Explain the Mechanism

Classic antidepressants don’t work for everyone and often take weeks to “warm up.” So scientists are simultaneously looking for ways to “tweak” neural circuits through other inputs — for example, through bodily stimuli that affect the brain. Acupuncture has long figured in clinical studies as an adjunctive therapy for stress and anxiety-depressive conditions, but the key question remains the same: what exactly does it change in the brain? This study is useful in that it links the behavioral effect to specific neurobiology. The study was published in the journal Theranostics.

What exactly was checked?

The authors took an established model of “chronic social stress” in mice — it reproduces important features of depression: avoidance of contacts, anhedonia (loss of interest in pleasant things), “learned helplessness”. Then they conducted a seven-day course of acupuncture at the LR3 (Taichong) point — it is located on the instep of the foot, between the 1st and 2nd metatarsal bones, and is traditionally considered “calming”. For the sake of purity of comparison, they also used a “false” point (control), where the needle should not have a specific effect.

Now comes the most interesting part. The researchers looked into the ventral hippocampus, especially the vCA1 region. This is the part of the hippocampus that in rodents is closely associated with emotions, anxiety, and stress response (unlike the dorsal, “memory” hippocampus). There they measured:

• live neuronal activity using fiber-optic calcium photometry (calcium flashes show how nerve cells “fire”);
• “architecture” of synapses - the number of dendritic spines on the processes of neurons (the more of them, the higher the potential for learning and network restructuring);
• molecular markers of synaptic plasticity: levels of BDNF (brain-derived neurotrophic factor), the active form of CaMKIIα, and AMPA receptor subunits (GluA1/GluA2), which are responsible for the main “fast” transmission of signals between neurons.

What happened?

Behavior. After a course of acupuncture, the mice behaved noticeably “healthier”: they were more likely to make social contact, showed interest in the sweet solution (reduced anhedonia), and “froze” less in “helplessness” tests. The “false” point did not produce such an effect — important because it eliminates the option “well, they just held the mouse and it felt better.”

Neural activity. Calcium photometry in vCA1 showed that the neuronal activity pattern shifted from a stress pattern to a more “normal” one. Translated from neurobiological terms, the circuit became more flexible and responsive, rather than stuck in the “minus motivation/plus anxiety” mode.

Synapses and molecules. The hippocampus of the “punctured” mice had more dendritic spines, increased BDNF levels, activated CaMKIIα, and AMPA receptors were more actively “pulled” to the synapse (their trafficking increased). All these changes are classic signs of increased glutamatergic transmission and plasticity. If you have heard that some new antidepressants “turn on plasticity” (make the brain more trainable and ready for restructuring), a similar picture is observed here, only the trigger is different.

Why is this important?

• The study links clinical observations with mechanisms: it’s not “we thought the mice got better,” but a set of objective markers at the level of neural networks and proteins.
• For the first time, it has been shown in such detail that stimulation of a single peripheral point can regulate a specific emotional circuit in the brain – the ventral hippocampus.
• Parallel to pharmacotherapy: Many of the rapid antidepressant effects are associated with rapid increases in AMPA transmission and increases in BDNF. Here we see a non-pharmacological route to similar changes - potentially combining with medications, reducing doses, or accelerating responses.

How can this work?

Acupuncture is not “meridian magic”, but rather bodily signals: the needle activates sensory nerve fibers, triggers vegetative and neuroimmune reflexes. It is known that such reflexes can reduce inflammatory activity, modulate vegetative tone and stress axes (hypothalamus - pituitary gland - adrenal glands). As a result, the “background” in the brain changes - the concentration of neurotransmitters, neurotrophins, the state of microglia - and this creates conditions for plasticity: synapses are more easily rebuilt, networks are stabilized. In this work, the authors show a specific implementation of this general idea - using vCA1 as an example.

What this does NOT prove (important limitations)

• These are mice. Their model of depression is good for research, but it is not equal to the human disease. In the clinic, everything is more complicated: concomitant diseases, a variety of symptoms, patient expectations, placebo effects, etc.
• One point, one protocol. The effect is shown for LR3 and a specific stimulation mode (daily, short course). It cannot be automatically transferred to "any acupuncture option".
• No comparison with drugs. The article does not directly "race" against SSRIs or, say, ketamine. It cannot say that it is better/faster/cheaper - as long as we know what works in principle and is accompanied by convincing neurobiology.
• The mechanism is probabilistic. We see the correlation "needle → plasticity → behavior improvement" and a good set of intermediate links. But in a real clinic, where there are many reasons, the effect can be variable.

And what could this mean for people?

If future clinical trials confirm similar changes in humans, we will have another drug-free way to speed up the rewiring of brain networks in depression, perhaps as an adjuvant to psychotherapy and/or medication. This is attractive for several reasons:

• low systemic risk of drug side effects;
• possibility of use in patients who cannot/are not suitable for antidepressants;
• potential for personalization (you can look for protocols that better “catch” the desired brain circuits).

But let us repeat: before this stage there is a long path of pilot and then randomized clinical trials with neuroimaging and objective markers.

Frequently asked questions

Where exactly is the LR3 point? On the back of the foot, between the 1st and 2nd metatarsal bones, closer to the ankle. Do not try to "puncture yourself" - this is part of the research protocol.

How many sessions were done to mice? Short course (week). For humans, the regimens will be selected and validated separately.

Can we “replace pills with needles”? This is the wrong question. If the effect is confirmed in humans, it would be more logical to use acupuncture in addition to proven methods – to enhance plasticity and speed up the clinical response.

Why the hippocampus? The ventral hippocampus in rodents is a key node of the “emotional brain.” Its plasticity is closely linked to anxiety, motivation, and stress response. In humans, the hippocampus is also involved in mood regulation.

What should scientists do next?

1. Repeat the experiment in independent laboratories and on other stress models.
2. Measure the duration of the effect: how long does the “plastic window” last, are maintenance sessions necessary.
3. Compare with pharmacotherapy and their combination.
4. Transfer to the clinic: small pilots in people with depression with registration of neuromarkers (fMRI/MEG, serum BDNF, etc.), then randomized studies.

Summary

This is a neat work that shows that pinpoint peripheral stimulation can trigger a cascade in the brain — from AMPA receptors and CaMKII to BDNF and new spines — and produce “antidepressant” behavior (in mice, for now). We are used to thinking that the brain can only be influenced by a “pill” or a “word.” It seems that there is a third way — through the body, with quite measurable changes in neural networks. Now it’s time for clinical evidence.