Mackenzie Dion

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nally, we have shown that the versatility of our imaging system can be used to flexibly navigate the inherent tradeoff between SNR and imaging FOV by performing high-SNR (up to ~14) neuronal population recordings with an over 10× increase in the number of collected photons per neuron per frame
A versatile platform for two-photon neuronal population voltage imaging across cortical depths | Nature Methods
calcium signals are only an indirect proxy for the membrane potential20,21,22,23, the actual quantity of interest; they are about 30–100 times slower than changes of membrane potential
A versatile platform for two-photon neuronal population voltage imaging across cortical depths | Nature Methods
he burst serves as an instructive, global “output occurred” signal, but only branches that were electrically primed immediately beforehand cross the Ca 2+ threshold and receive a durable biochemical trace. In this way, transient, branch - specific synaptic activation is selectively tagged when it contributes to successful spiking output, providing a high - fidelity mechanism for associative, branch - resolved lea rning without requiri ng dendrites to generate frequent independent spikes. This view is consistent with theories in which dendritic compartments supply local instructive signals that…
A dendrite-resolved, in vivo transfer function from spike patterns to dendritic Ca2+
Our data instead support a model of gated back - propagation in which somatic spiking provides a global broadcast to the dendritic arbor, while the dendrite locally determines whether that broadcast is converted into Ca 2+ influx.
A dendrite-resolved, in vivo transfer function from spike patterns to dendritic Ca2+
The rarity of isolated dendritic Ca 2+ events suggests that, at least in this cell type and our measurement conditions , the dendrite s typically do not act as autonomous calculator s .
A dendrite-resolved, in vivo transfer function from spike patterns to dendritic Ca2+
despite the biological complexity of Ca 2+ handling, local Ca 2+ transients are accurately captured by a compact, channel - inspired transfer function of the local voltage waveform, providing a quantitative framework for interpreting dendritic Ca 2+ imaging.
A dendrite-resolved, in vivo transfer function from spike patterns to dendritic Ca2+
in this behavioral context, dendritic Ca 2+ signals largely reflect the variable penetration of back - propagating action potentials, with complex spikes disproportionately driving distal apical Ca 2+ .
A dendrite-resolved, in vivo transfer function from spike patterns to dendritic Ca2+
On this characterization of causality, it should be clear that many familiar examples of computational models can be assimilated to causal models: all we need is some way to carve the model into natural causal variables, together with a suitable notion of intervention on the model.
[2508.11214] How Causal Abstraction Underpins Computational Explanation
Meanwhile, we adopt a broadly interventionist approach to causal explanation, whereby explaining why A is a matter of identifying causal difference- makers for A , answering “what-if-things-were-different” questions about A , and facilitating some degree of (at least in-principle) manipulation and control of A (Woodward, 2003).
[2508.11214] How Causal Abstraction Underpins Computational Explanation
Achieving this goal required selecting a 2P excitation wavelength (1135 nm) that efficiently populated the intermediate state and a dye that was efficiently excited at this wavelength while also undergoing efficient FRET with the opsin, and applying scan patterns which re- visited each molecule frequently enough to overcome relaxation of the voltage-sensitive intermediates.
Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
We hypothesized that the previously reported poor 2P voltage sen- sitivity in opsin-based GEVIs (26, 39) might arise from failure to populate voltage-sensitive photocycle intermediates (Fig. 2F). This hypothesis is consistent with our observations that sufficient 1P illumination was required to observe 1P voltage sensitivity and with the much lower per-molecule excitation rate of 2P versus 1P excitation
Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
For both GEVIs, the voltage sensitivity was the greatest (in absolute value), and the illumination intensity dependence leveled off around 10 to 30 mW/mm 2 . By good fortune, this intensity re- gime is typically used in neural recordings because it produces high- enough per-cell count rates to observe neural dynamics over shot noise.
Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
The light used to excite the FRET donor can also interact with the opsin acceptor directl
Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
In Förster resonance energy transfer (FRET)–opsin GEVIs, voltage-dependent changes in the efficiency of FRET from an attached fluorophore to the opsin lead to modulation of the fluorophore brightness (Fig. 1A
Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
For example, correlated activity in cortical ensembles at fast timescales has been proposed to be a key means of encoding and computing aspects of sensory stimuli (Salinas and Sejnowski, 2001).
Cracking the Function of Layers in the Sensory Cortex: Neuron
Achieving cellular resolution, millisecond precision voltage imaging of cortical layers would allow us to address major questions about cortical computation as it might be implemented by each layer.
Cracking the Function of Layers in the Sensory Cortex: Neuron
We suspect that neural ensembles composed of co-active neurons distributed across layers are the major substrate of cortical computation.
Cracking the Function of Layers in the Sensory Cortex: Neuron
In the framework of statistical inference, cortical circuits encode a generative model of the sensory environment, and recurrent interactions between cortical processing stages compare the expectations of the internally generated model with incoming data from the sensory apparatus (Bastos et al., 2012).
Cracking the Function of Layers in the Sensory Cortex: Neuron
2) In the absence of somatic AP firing, in apparently silent neurons the local dendritic spikes can change the long-term efficacy of local synaptic inputs (Golding et al. 2002). So, in the absence of somatic APs, local dendritic spikes provide necessary depolarization of the postsynaptic membrane, thus satisfying the Hebbian requirement for long-term potentiation (Lisman 1989). 3) Subthreshold depolarizations are known to propagate into the axon, alter the axonal membrane excitability, and potentially cause changes in the coupling efficiency with the downstream members of the neuronal network …
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
Nerve cells that appear silent in single-unit recordings (no AP firing) may be experiencing dramatic membrane potential fluctuations in the form of localized dendritic potentials (Hausser et al. 2000). Excitatory synaptic inputs can trigger large depolarizations and regenerative potentials in remote segments of thin dendritic branches (Hausser et al. 2000).
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
GEVI-based approaches enable 1) efficient detection of neural ensembles, 2) efficient detection of network properties, and 3) detection of rhythmic and synchronized activities (orchestration) and exploration of their underlying circuit mechanisms. Thus GEVI-based optical imaging will be a “game-changer” for the study of large-scale dynamics, by allowing neuroscientists to selectively monitor the electrical synaptic INPUT to and OUTPUT from neurons of a chosen genetic type or connectivity pattern in behaving animals while observing the rich repertoire of electrical activity in those neurons.
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
While GECIs are completely ineffective reporters of subthreshold physiological states, GEVIs can detect slow components of membrane potential transients (depolarization envelopes) (Fig. 1A).
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
Neuronal oscillatory activities may be subthreshold for activation of voltage-gated calcium channels (and hence are not associated with detectable Ca2+ transients) but could facilitate synchronous interactions by biasing neurons to discharge within the same time frame (Engel et al. 2001; Petersson and Fransen 2012; Yu and Ferster 2010).
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
Some major cell classes (GABAergic interneurons) generate very narrow APs that are not accompanied by large Ca2+ transients (Evstratova et al. 2011; Franconville et al. 2011). Hyperpolarizing events and subthreshold depolarizing synaptic events are not associated with large Ca2+ influxes.
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
GEVI signals largely represent synaptic INPUT arriving into a neural circuit, while GECI signals (in large-scale imaging experiments) represent AP OUTPUT generated in the neural circuit. Integration of synaptic inputs comprises the first stage of neuronal information processing (Poirazi et al. 2003). Monitoring the INPUT into a neural circuit via a GEVI is necessary for investigating neuronal computations, while AP monitoring via GECIs only informs about the result of the computation.
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
) GEVIs enable measurements of voltage transients that are refractory to Ca2+ imaging (that is to say, Ca2+ imaging is blind to some essential neuronal signals). 2) In addition to being blind to some electrical phenomena, Ca2+ imaging is also contaminated with signals remotely related to the neuronal membrane potential (Table 1). 3) GEVI imaging should be conceptualized differently from Ca2+ imaging (each recording mode GECI and GEVI has a specific significance to the INPUT-OUTPUT feature of the neural circuit; see below).
Voltage imaging to understand connections and functions of neuronal circuits | Journal of Neurophysiology | American Physiological Society
ns: Whatever cognitive processes subserve the introspective reporting are going to generate the same signals -- including misleading signals, if experience is absent -- as they would in the case where experience is present and accurately reported. Thus, unreliability would simply be what we should expect.
An Objection to Chalmers's Fading Qualia Argument
Ex hypothesi, the silicon backup gives rise to non-red experience but delivers to the Introspection Module exactly the same inputs as that module would normally receive from an organic brain part experiencing red. This is exactly the type of case where we should expect introspection to be unreliable.
An Objection to Chalmers's Fading Qualia Argument
An adequate defense of the Fading Qualia argument will require careful justification of why someone skeptical about the seemingly introspective judgments of an entity whose brain is entirely silicon should not be similarly skeptical about similar seemingly introspective judgments that occur throughout the gradual replacement process. As it stands, the argument lacks the necessary resources legitimately to assuage the doubts of those who enter it uncertain about whether consciousness would be present in a neuron-for-neuron silicon isomorph.
The Splintered Mind: An Objection to Chalmers's Fading Qualia Argument
S ituations of gradual neural replacement might be exactly the type of situation in which introspection should be expected to fail. Whatever causal processes lead up to the report s are guaranteed to generate the same report s regardless of whether consciousness actually continues to be present
[2510.09858] AI and Consciousness
gamma synchrony is a local phenomenon. Its strength quickly decays to zero for neurons separated by distances larger than a few mm. 49–51 Gamma synchrony can therefore not group image ele- ments that are represented by neurons with a larger separatio
Solving the binding problem: Assemblies form when neurons enhance their firing rate-they don't need to oscillate or synchronize
Incremental grouping works for unfamiliar shapes, which are not represented as base groupings and can hence only be rep- resented in a distributed manner.
Solving the binding problem: Assemblies form when neurons enhance their firing rate-they don't need to oscillate or synchronize
Visual motion blindness or akinetopsia is a rare disorder in which the visual world comes out as if in successive still photographs (Zihl, von Cramon, & Mai, 1983; Zeki, 1991).
Binding and the Phenomenal Unity of Consciousness
his presupposes an underlying mechanism that locates the right colour in the right shape and keeps both moving together.
Binding and the Phenomenal Unity of Consciousness
consciousness-related binding: How are internal subjective percepts, as phenomenally unified entities, constructed by the brain as neural entities, considering that the neural mechanisms necessary for creating different phenomenal contents are distributed all around the cortex?
Binding and the Phenomenal Unity of Consciousness
Binding is rather seen as any process or mechanism that in some sense recovers the unity of the stimulus object; a unity objectively existing out there in the physical stimulus. I call this con- ception of binding stimulus-related binding
Binding and the Phenomenal Unity of Consciousness
Rosa Cao [ 72 ] points out that in the biological brain, functional properties are not nomologi- cally independent of material properties. The functions of different processes of the brain (including the metabolic and informational processes) are not easily decomposed, but deeply intertwined and running simultaneously. Hence, she argues, for example, how Chalmers’ neural replacement scenario [ 25 ], which is meant as a thought experiment arguing in favor of computational functionalism in which a replacement of neuron by neuron to silicon maintains the same functional organization, cannot reall…
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
here are things one can do with an analog device that one cannot do with a digital computer
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
By design, digital computers are engineered to ignore their physical underlying analog properties. Brains, in contrast, rely on analog processing (whether it is the geometrical location of the synapses, the exact timing of an action potential, or the frequency of an electromagnetic field).
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
By design, digital computers are engineered to ignore their physical underlying analog properties. Brains, in contrast, rely on analog processing (whether it is the geometrical location of the synapses, the exact timing of an action potential, or the frequency of an electromagnetic field).
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
We also find objections that timing, parallelism or synchronicity constraints on a computational architecture might matter for consciousness
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
At this level, for example, we find one version of the objection that only analog systems can be conscious (because, though the processes in the brain that realize a mind are computational processes, their analogicity is essential).
[2511.16582] Consciousness in Artificial Intelligence? A Framework for Classifying Objections and Constraints
(By contrast, many processes, such as cooking, cleaning, and exploding, are deﬁned in terms of speciﬁc physical alterations of speciﬁc substances. They are not medium independent; hence, they are not computations.)
Neural Computation and the Computational Theory of Cognition
Ca2+ imaging fails to reveal individual action potentials in many fast-spiking cell types, poorly captures sub-threshold membrane voltage dynamics and offers insufficient temporal information to permit studies of action potential timing to better than ~50–100 ms.
Imaging neural spiking in brain tissue using FRET-opsin protein voltage sensors | Nature Communications
Unfortunately, calcium indicators are poor at reporting subthreshold activity including neuronal inhibition. Being able to monitor both activation and inhibition is critical for such ailments as PD and TS since the balance between these two types of activities has been altered.
Frontiers | Visualizing Oscillations in Brain Slices With Genetically Encoded Voltage Indicators
Having an optical readout of activity from different components of neuronal circuits affected by DBS would help explain the therapeutic mechanism leading to improved clinical outcomes.
Frontiers | Visualizing Oscillations in Brain Slices With Genetically Encoded Voltage Indicators
The 2P-SPIM approach is capable of even faster acquisition speed, beyond video rate: we imaged the beating heart inside a live 5.4-day-old zebrafish embryo using 50 mW total excitation power, achieving cellular resolution at 70 frames s−1 (limited by camera readout speed) for a 400 pixels × 400 pixels field of view (11.2 million pixels s−1, comparable to rates achieved by 1P-SPIM imaging of similar samples at younger developmental stages12), capturing the fast motion of the heart walls and valve leaflets without any sign of phototoxicity (Supplementary Fig. 8 and Supplementary Video 7)
(PDF) Deep and fast live imaging with two-photon scanned light-sheet microscopy
Your heart is like a great river after a long spell of rain, full to the banks. All signposts that once stood on the ground are gone, inundated and carried away by that rush of water. And still the rain beats down on the surface of the river. Every time you see a flood like that on the news you tell yourself: That's it. That's my heart.
Excerpt: Kafka On The Shore : NPR
with epitopes to enable post hoc multiplexed antibody staining.
Spatial Multiplexing of Fluorescent Reporters for Imaging Signaling Network Dynamics - ScienceDirect
As long as the clusters stayed stationary during the live-cell imaging, identifying the signals could be done post hoc, after the live-cell imaging was over, by using highly multiplexed fixed-cell imaging methods to identify distinct tags bound to each of the different reporters (e.g., serial antibody staining against distinct immunoepitopes fused to each of the distinct fluorescent reporters
Spatial Multiplexing of Fluorescent Reporters for Imaging Signaling Network Dynamics - ScienceDirect