What leads the pace of novel scientific discovery? Scientist Sydney Brenner famously said:
Progress in science depends on new techniques, new discoveries and new ideas, probably in that order.
Recently, Professor Ed Boyden from MIT tweeted Brenner’s quote, and a discussion ensued about whether or not the quote actually reflected the way science progresses, or at least the way it should progress. Most agreed, but some disagreed, like NeuroSyntheSys who said:
Respectfully disagree. IMHO real revolutionary science would start with truly novel ideas. E.g. Darwin, Einstein, etc. Ideas shall lead.
But others pointed out examples of how technology led to new ideas, such as optogenetics, RNAi, and CRISPR. Indeed, my experience is that scientists push questions as far as existing technologies will take them, until they need to either develop new methods or wait for others to do so and jump on collaborating with them.
Here we highlight ten papers featuring Inscopix miniature microscope technology, nVista, that collectively show how groundbreaking technological advances can lead to new foundational knowledge about the brain. These select papers dissect the neural circuit basis of learning and memory, and capitalize on Inscopix's prowess in enabling the imaging of large-scale neural dynamics with cell-type specificity and single-cell resolution during unrestrained naturalistic animal behavior. The findings obtained could not have been possible without the ability to record during free behavior, and the pairing of imaging with activity manipulation methods in some cases.
Here are the links and summaries of the 10 learning and memory papers:
Figure: Summary of diverse brain regions, both superficial and deep, imaged using Inscopix miniature microscope technology to study learning and memory. The numbers refer to the papers listed in this post.
(1) Long-term dynamics of CA1 hippocampal place codes by Ziv et al. 2013. Nature Neurosci.
- Imaged a record 1,200 hippocampal CA1 neurons simultaneously for 45 days.
- A surprising result that retention of spatial information in CA1 combines stable place field locations with ~15–25% odds an individual cell will recur in the place code, contrary to prior long-term recordings of much smaller populations of cells that stressed place-field stability.
(2) Entorhinal cortical ocean cells encode specific contexts and drive context-specific fear memory by Kitamura et al. 2015. Neuron
- Imaged Ocean and Island cell populations in medial entorhinal cortex
- Ocean cells, but not Island cells, exhibit context-specific Ca2+activity and drive context exposure-dependent activation of dentate granule (DG) cells and CA3 hippocampal cells.
(3) Hippocampal ensemble dynamics timestamp events in long-term memory by Rubin et al. 2015. eLife
- Used imaging to study the binding and separation of CA1 episodic codes over timescales of days–weeks and across different environments.
- Their findings of coding dynamics over timescales of days are consistent with a key feature of episodic memory—that each experience is uniquely encoded.
(4) Ventral CA1 neurons store social memory by Okuyama et al. 2016. Science
- Imaged PFC engram cells during foot shock stimulus and resultant freezing behavior to identify engram cells
- Both the proportion of activated vCA1 cells and the strength and stability of the responding cells are greater in response to a familiar mouse than to a previously unencountered mouse.
- vCA1 neurons and their NAc shell projections are a component of the storage site of social memory.
(5) Distinct hippocampal pathways mediate dissociable roles of context in memory retrieval by Xu et al. 2016. Cell
- Imaged in ventral Hippocampus (vHC)
- vHC projection to the Basolateral Amygdala is required for contextual fear memory retrieval
- vHC projection to the Central Amygdala is necessary for context-dependent cue fear memory retrieval
(6) Neural ensemble dynamics underlying a long-term associative memory by Grewe et al. 2017. Nature
- Imaged more than 3,600 BLA cells across 6 days
- BLA ensembles of neurons implement a supervised learning algorithm to encode the CS–US association
(7) Engrams and circuits crucial for systems consolidation of a memory by Kitamura et al. 2017. Science
- Imaged prefrontal cortex for 15 days
- Found that stimulus input into the PFC is crucial for the generation of PFC engram cells.
(8) Delay of activity of specific prefrontal interneuron subtypes modulates memory-guided behavior by Kamigaki et al. 2017. Nature Neurosci.
- Imaged 3 different types of dmPFC GABAergic interneurons
- dmPFC is a crucial component of the short-term memory network
- Activation of VIP neurons plays a key role in memory retention
(9) Dorsal-CA1 Hippocampal neuronal ensembles encode nicotine-reward contextual associations by Xia et al. 2017. Cell Reports
- They dissect neural activity in dorsal CA1 while mice freely behave and form a nicotine place preference.
- Reveals specificity of a nicotine-paired CA1 ensemble that predicts and is active during nicotine conditioned place preference expression.
(10) Distinct neural circuits for the formation and retrieval of episodic memories by Roy et al. 2017. Cell
- Imaged in both CA1 of the hippocampus and the dorsal subiculum (Sub)
- Dorsal Sub neurons exhibit enhanced neuronal activity during hippocampal memory retrieval
- Episodic memory encoding uses primarily the direct dCA1/EC5 circuit, while episodic memory retrieval uses primarily the indirect dCA1/dSub/EC5 circuit.
- Demonstrates distinct contributions of dCA1 and dorsal Sub cells to memory encoding and memory recall, respectively.