Neurons that Fire Together, Don’t Always Wire Together

Summary: Researchers have identified a new rule of connectivity for neurons in the neocortex, contradicting the popular belief “neurons that fire together, wire together”.

Source: Sainsbury Wellcome Center.

As the adage goes “neurons that fire together, wire together,” but a new paper published today in Neuron demonstrates that, in addition to response similarity, projection target also constrains local connectivity.

Researchers from the Sainsbury Wellcome Centre have been looking to elucidate the rules of connectivity of neurons in the neocortex with the long term goal of building models to understand how the brain makes computations and how properties of neurons arise from the structure of their connections.

Traditionally, neurons that project within the cortex have been thought to be homogeneous, particularly in comparison to neurons that project from the cortex to other areas of the brain, but it is becoming clear that these cortical-cortical cells are actually quite diverse.

In the study, Kim, Znamenskiy et al. examined the connections between different types of excitatory neurons in the primary visual cortex (V1) that project to two higher visual areas, anterolateral (AL) and posteromedial (PM), in mice.

Building on previous research, the study found biases between the cell populations: one population preferred fast moving, coarser visual stimuli and the other population preferred slow moving, finer-scale visual stimuli. But many neurons in both populations shared their preference for visual stimuli.

Importantly, the researchers found that cells with the same projection target (e.g. the AL-projecting neurons) made connections with one another but rarely made connections with their PM-projecting neighbours. “Cells projecting to different targets are excluded from interacting with each other, despite being neighbours. This new ‘exclusion’ principle of connectivity is puzzling given that these neurons frequently respond together to the same sensory stimuli”, says Tom Mrsic-Flogel, a senior author on the study.

Why might it be that there is very little cross-talk between these two output channels within visual cortex? Previous work from the Mrsic-Flogel lab showed that you can predict which cells in visual cortex connect by looking at their responses. Cells that are active at the same time and respond to similar types of visual stimuli are much more likely to connect to each other. However, this does not hold for AL- and PM-projecting cells which are functionally quite similar but somehow avoid making connections with one another. One possibility is that the signals transmitted by these cell populations are kept separate to allow independent control of these output pathways.

visual cortex neurons
Primary visual cortex neurons projecting to higher visual area AL. image is credited to Sainsbury Wellcome Centre.

If they fire together but are not wiring together, how are these parallel channels to AL and PM are set up? One future avenue is to explore whether there are molecular mechanisms that dictate these specific wiring rules. The researchers will also explore how widespread these ‘hardwired’ patterns of connectivity are in the brain.

Petr Znamenskiy, joint first author on the paper, commented on the importance of the work: “The flow of information in the brain is defined by where individual neurons get their inputs and where they send their outputs. To gain a mechanistic understanding of neural computations, we need to know these rules of connections.”

Future research will focus on the functions of these independent output channels and how individual neurons decide what inputs to select and where to send their axons. Through further understanding of the molecular mechanisms of these rules, the researchers hope to piece together the processes that govern the brain’s intricate wiring.

About this neuroscience research article

Funding: This research was supported by the Gatsby Charitable Foundation, Wellcome, European Research Council and the Swiss National Science Foundation.

Source: April Cashin-Garbutt – Sainsbury Wellcome Center
Publisher: Organized by
Image Source: image is credited to Sainsbury Wellcome Centre.
Original Research: Abstract for “Segregated Subnetworks of Intracortical Projection Neurons in Primary Visual Cortex” by Mean-Hwan Kim, Petr Znamenskiy, Maria Florencia Iacaruso, and Thomas D. Mrsic-Flogel in Neuron. Published November 8 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Sainsbury Wellcome Center”Neurons that Fire Together, Don’t Always Wire Together.” NeuroscienceNews. NeuroscienceNews, 8 November 2018.
<>.[/cbtab][cbtab title=”APA”]Sainsbury Wellcome Center(2018, November 8). Neurons that Fire Together, Don’t Always Wire Together. NeuroscienceNews. Retrieved November 8, 2018 from[/cbtab][cbtab title=”Chicago”]Sainsbury Wellcome Center”Neurons that Fire Together, Don’t Always Wire Together.” (accessed November 8, 2018).[/cbtab][/cbtabs]


Segregated Subnetworks of Intracortical Projection Neurons in Primary Visual Cortex

The rules by which neurons in neocortex choose their synaptic partners are not fully understood. In sensory cortex, intermingled neurons encode different attributes of sensory inputs and relay them to different long-range targets. While neurons with similar responses to sensory stimuli make connections preferentially, the relationship between synaptic connectivity within an area and long-range projection target remains unclear. We examined the local connectivity and visual responses of primary visual cortex neurons projecting to anterolateral (AL) and posteromedial (PM) higher visual areas in mice. Although the response properties of layer 2/3 neurons projecting to different targets were often similar, they avoided making connections with each other. Thus, projection target, in addition to response similarity, constrains local synaptic connectivity of AL and PM projection neurons. We propose that reduced crosstalk between different populations of projection neurons permits independent function of these output channels.

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  1. It does not matter if it wires together or fire together because science will never understand the reality as science is based on deduction. If I give you a flower and ask you about it, the scientist mind will try to deduct the flower into pieces, study about a part and explain about the whole has been the problem of science. We want a sharp intellect because the ego(mind) will deduct it and try to explain the whole. When that had happened, what science would have missed is, It would have failed to see the flower as a WHOLE. Today it’s Hebb, tomorrow is Cajal. That’s where the egoistic science will never understand about life as a WHOLE as it’s trying to make the bigger picture by studying the parts. It’s about time we brought spirituality to neuroscience. Sounds crazy, but wait till we are all 60.
    ~from China

  2. Not a new finding but good to see replication. e.g Honey CJ, Thivierge JP, Sporns O. Can structure predict function in the human brain? NeuroImage 2010;52:766–776. [PubMed] Functional networks often show organization different from DTI studies would suggest. fMRI defined networks do not have the time resolution of EEG/QEEG identified functional communication; cf Roberto D Pascual-Marqui’s study of key nodes in the Default Mode Network organized into four functional sub-units blurred together by low time resolution of the fMRI.

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