Your response has fascinated me. Listening to podcasts, I have always so dearly wanted to know what Michael or others meant specifically by "Voltage gradient". These have given me great topics to further conduct research into, with my currently fundamental neuroscience knowledge rooted in understanding of memory, learning and Action Potentials.

I have tried to further this understanding with LLMs but am ofcourse not sure if what they are saying is correct (given the understudied and sparse nature of this research).

If you had a moment to help me understand what exactly these voltage gradients are, how they differ from action potentials, and to tie these to the processes at the cellular level to the larger system, I would be so grateful (for example, is SSH used in limb regeneratio nas well as pattern formation? How? Is it dormant in normal limbs? Which cells, in the limb or in the brain? Which research articles found this? I am fascinated!).

In the meantime, here is what Claude told me. I am not sure if it is accurate, I get a sense of "sweeping under the rug":

"Specific ion channels and gradients:

During limb regeneration in amphibians like salamanders, one of the key ion channels involved is the V-gated proton channel (Hv1).
The wound epidermis cells at the amputation site become depolarized due to the influx of protons (H+) through the Hv1 channels, creating a localized region of elevated intracellular pH.
This pH gradient, or proton gradient, is believed to be a crucial signal that initiates and guides the regenerative process.
Other ion gradients, such as calcium (Ca2+) and sodium (Na+), have also been implicated in regulating various stages of limb regeneration, but the proton gradient is particularly well-studied.

Reaching and influencing cells:

The voltage gradients or ion gradients can propagate through tissues and reach distant cells due to a phenomenon called bioelectric signal propagation.
Cells are electrically coupled through gap junctions, which allow for the passive spread of ions and small molecules between cells.
This electrical coupling enables the voltage or ion gradients to be transmitted from the source cells (e.g., wound epidermis) to the target cells (e.g., blastema) over long distances.
The gradients can influence gene expression, cell proliferation, and cell migration in the target cells, guiding the regenerative process.

Pattern effects and limb regeneration processes:

The specific patterns of voltage or ion gradients are crucial for determining the outcomes of regeneration, such as the completeness and proper patterning of the regenerated limb.
For example, manipulating the proton gradient can lead to the formation of supernumerary (extra) limbs or alteration of the limb pattern.
The voltage gradients are involved in various stages of limb regeneration, including wound healing, blastema formation, patterning, and differentiation of cells into specific tissue types (e.g., bone, muscle, nerves).

Gradient vs. specific voltage measurement:

The term "voltage gradient" or "bioelectric field" refers to a spatial pattern of voltage differences, rather than a singular voltage measurement at a specific point.
It's similar to a topographic map, where the voltage (or ion concentration) varies across different regions, creating a gradient or slope.
In contrast, an action potential or membrane potential refers to a specific voltage difference across the cell membrane at a given point in time.
The voltage gradient is a long-range signal that provides positional information and guides cellular behaviors during regeneration, while action potentials are localized electrical signals involved in neuronal communication and muscle contraction.

The voltage gradient, or bioelectric field, is a spatially distributed pattern of voltage differences that serves as a long-range instructive signal for coordinating cellular activities during regeneration. It is distinct from a singular voltage measurement or an action potential, as it represents a gradient or slope of voltage across different regions, providing positional cues and guiding the regenerative process."