Evidence
Evidence without direct access: pdf
I. Retrodictive Evidence
Retrodiction—reasoning backward from observed outcomes after the hypothesis—is just as powerful in validating a proposed solution. The primary goal here is to assess whether new research findings can be explained in terms of the IPL mechanism in an interconnected manner.
A. In physiological conditions & artificial systems
Liu S, Pletenev A, Haefner RM, Snyder AC (2026 February) Task learning increases information redundancy of neural responses in macaque visual cortex. Science. 391(6789):1029-1035. PubMed
Vicarious body maps bridge vision and touch in the human brain. Hedger N, Naselaris T, Kay K, Knapen T (2026 February) Nature. 650(8100):173-181. PubMed
Building compositional tasks with shared neural subspaces. Tafazoli S, Bouchacourt FM, Ardalan A, Markov NT, Uchimura M, Mattar MG, Daw ND, Buschman TJ (2026 February) Nature. 650(8100):164-172. PubMed
Large-scale cortical functional networks are organized in structured cycles. van Es MWJ, Higgins C, Gohil C, Quinn AJ, Vidaurre D, Woolrich MW (2025 Aug) Nat Neurosci. 27. PubMed
Left-right-alternating theta sweeps in entorhinal-hippocampal maps of space. Vollan AZ, Gardner RJ, Moser MB, Moser EI (2025 Mar) Nature. 639(8056):995-1005. PubMed
Hippocampal encoding of memories in human infants. Yates TS, Fel J, Choi D, Trach JE, Behm L, Ellis CT, Turk-Browne NB (2025 Mar 21) Science. 387(6740):1316-1320. PubMed
Human olfactory perception embeds fine temporal resolution within a single sniff. Wu Y, Chen K, Xing C, Huang M, Zhao K, Zhou W (2024) Nat Hum Behav. 8(11):2168-2178. PubMed
Chromatin plasticity predetermines neuronal eligibility for memory trace formation. Santoni G, Astori S, Leleu M, Glauser L, Zamora SA, Schioppa M, Tarulli I, Sandi C, Gräff J (2024) Science. PubMed
Higher-order interactions between hippocampal CA1 neurons are disrupted in amnestic mice. Yan C, Mercaldo V, Jacob AD, Kramer E, Mocle A, Ramsaran AI, Tran L, Rashid AJ, Park S, Insel N, Redish AD, Frankland PW, Josselyn SA (2024) Nat Neurosci. PubMed
Barcoding of episodic memories in the hippocampus of a food-campus of a food-caching bird. Chettih SN, Mackevicius EL, Hale S, Aronov D (2024) Cell. 187(8):1922–1935.e20. PubMed
A ubiquitous spectrolaminar motif of local field potential power across the primate cortex. Mendoza-Halliday D, Major AJ, Lee N, Lichtenfeld MJ, Carlson B, Mitchell B, Meng PD, Xiong YS, Westerberg JA, Jia X, Johnston KD, Selvanayagam J, Everling S, Maier A, Desimone R, Miller EK, Bastos AM (2024) Nat. Neurosci. PubMed
Evidence for long-term potentiation in phospholipid membranes. Scott HL, Bolmatov D, Podar PT, Liu Z, Kinnun JJ, Doughty B, Lydic R, Sacci RL, Collier CP, Katsaras J. (2022) PNAS. 119(50):e2212195119. PubMed
Entorhinal cortex directs learning-related changes in CA1 representations Grienberger and Magee (2022) Nature. 611(7936):554-562. PubMed
Invariant stimulus decoding using correlated neuronal fluctuations. Ebrahimi et al., (2022) Nature. 605(7911):713-721. PubMed
Mosquito brains encode unique features of human odour to drive host seeking. Zhao et al., (2022) Nature. May 605(7911):706-712. PubMed
Synaptic correlates of associative fear memory in the lateral amygdala. Choi et al., (2021) Neuron. 109(17):2717-2726. PubMed
Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin. Christoffel et al., (2021) PNAS.118(24):e2106648118. PubMed
Drift in the set of neurons in the primary olfactory cortex that fire in response to an odour. Schoonover et al., (2021) Nature. 594(7864):541-546. PubMed
Largest class of neurons in the visual cortex is not reliably responsive to any of the visual stimuli. de Vries et al., (2020) A large-scale standardized physiological survey reveals functional organization of the mouse visual cortex. Nat Neurosci. 2020 Jan;23(1):138-151. PubMed
Artificial firing of a neuron leads to firing of a set of neurons of the same neuronal order. Chettih SN, Harvey CD (2019) Single-neuron perturbations reveal feature-specific competition in V1. Nature. PubMed
Memory retrieval occurs at a frequency of oscillating extracellular potentials similar to that was present during learning. Vaz AP, Inati SK, Brunel N, Zaghloul KA (2019) Coupled ripple oscillations between the medial temporal lobe and neocortex retrieve human memory. Science. 363:975-978. PubMed
Hotspots of dendritic spine turnover facilitate clustered spine addition and learning and memory. Frank AC, Huang S, Zhou M, Gdalyahu A, Kastellakis G, Silva TK, Lu E, Wen X, Poirazi P, Trachtenberg JT, Silva AJ (2018) Nat Commun. 9(1):422. PubMed
Synapse-specific representation of the identity of overlapping memory engrams. Abdou K, Shehata M, Choko K, Nishizono H, Matsuo M, Muramatsu SI, Inokuchi K (2018) Science. 360(6394):1227-1231. Article
Heterogeneity of neurons in the cortex Studies of cortical neurons show significant heterogeneity in transcriptomic analyses (Tasic et al., 2016
PubMed; Cembrowski et al., 2016 PubMed; Tasic et al., 2018 PubMed; Hodge et al., 2019 PubMed). Evidence by re-interpretation
Spine depolarization without dendritic depolarization. Beaulieu-Laroche L and Harnett MT. 2018. Dendritic spines prevent synaptic voltage clamp. Neuron 97(1): 75–82.e3. PubMed
Dendritic calcium spikes that are related to behavior and cognitive function
Regenerative spikes at the dendritic arbor - a mechanism for internal sense of a place that reflects binding at the time of learning
B. In pathological conditions
Spread of epileptic activity. Jefferys JG (2014) How does epileptic activity spread? Epilepsy Currents. 14(5):289-290. PubMed
Heterogeneity of clinical and pathological findings in Alzheimer's disease
II. Predictions
1. Dendritic spines have surface areas ranging from 0.61 to 3.14 μm2. IPLs are expected to have areas of only few squire nanometers. Hydration exclusion, which is the initial stage of IPL reverses back quickly. This can be verified by developing dedicated techniques (Vadakkan, 2015, 2016, 2019b).
2. IPLs formed by partial and complete hemifusion can be verified using high-resolution microscopes (Vadakkan, 2016, 2019b).
3. Injecting different neurons, whose spines can undergo IPLs, with different lipophilic fluorophores to stain their membranes followed by repetition of an associative learning event is expected to demonstrate partial and complete hemifusion stages of IPL formation (Vadakkan, 2016, 2019b).
4. A robust mechanism by specific SNARE proteins (such as Q-SNAREs) will arrest membrane hemifusion (possibly by interactions with postsynaptic proteins such as complexin and syntaxin-3) (Vadakkan, 2019b).
5. Stabilization of hemifusion stage of IPLs by different mechanisms will be present. Presence of stabilized IPLs formed by complete hemifusion can be verified by electron microscopy (Vadakkan, 2019b).
6. Since repeated associative learning can induce long-term changes by the introduction of transmembrane proteins across the hemifused membrane segments, studies can be undertaken to verify their presence (Vadakkan, 2016).
7. Artificially changing the frequency of oscillating extracellular potentials in the olfactory glomerulus in the fly Drosophila will alter smell perception (Vadakkan, 2015; 2019b).
8. Blocking large number of inter-postsynaptic functional LINKs either in the visual cortex or in the glomerulus is expected to alter the horizontal component of oscillating potentials, which will alter the frequency of oscillating potentials and disrupt visual or olfactory perception respectively (Vadakkan, 2015).
9. Advanced real-time microscopic examination may provide evidence for the reversible, yet stabilizable nature of the inter-postsynaptic membrane hemifusions both during LTP induction and associative learning. A reversal of this process can be tested during the reversal phase after LTP induction (Vadakkan, 2016; 2019a).
10. For a given distance between the stimulating and recording electrodes, strength of LTP induced at different locations will depend on the number of inter-spine LINKs formed during the delay time after stimulation (Vadakkan, 2019b).
11. Strength of LTP induced at different locations of the nervous system using a fixed stimulation intensity for a given distance between the stimulating and recording electrodes depends on 1) the number of converging inputs, 2) spine density, 3) number of inter-LINKed spines formed during the delay period after the stimulation, which is responsible for conducting current to the recording electrode, 4) lipid composition of spine membranes, and 4) properties of ECM at the inter-spine region (Vadakkan, 2019a).
12. Kindling will generate inter-spine fusion in the synapse-rich area between the electrodes (Vadakkan, 2019b)
13. Kindling induced at the Schaffer collateral area is expected to produce more inter-spine fusions than by LTP induction at the same location. Area of inter-spine fusion between the spine surfaces is expected to be larger following kindling than LTP stimulation. Kindling-generated large inter-spine fusions are expected to be irreversible when compared to the mostly small and reversible IPLs formed by LTP-inducing stimulus (Vadakkan, 2019a).
14. Different types of IPLs will occur following LTP stimulation. A reversal of this process will occur during the reversal phase following LTP induction (Vadakkan, 2019b).
References
Vadakkan KI (2015) A framework for the first-person internal sensation of visual perception in mammals and a comparable circuitry for olfactory perception in Drosophila. Springerplus. 4:833.
Vadakkan KI (2016) The functional role of all postsynaptic potentials examined from a first-person frame of reference. Rev Neurosci. 27(2):159-84.
Vadakkan KI (2019a) A potential mechanism for first-person internal sensation of memory provides evidence for the relationship between learning and LTP induction. Behav Brain Res. 360:16-35.
Vadakkan KI (2019b) From cells to sensations: A window to the physics of mind. Phys Life Rev. 31:44-78.