news and views

As with all pathways in biology, the sequence to the damage caused by the C9orf72 expan- covering explanations for the loss of neurons
of events described by the authors is embedded sions. This would lead to the prediction that in a wide range of more common neurode-
in a complex cellular environment that inter- we should be more vulnerable to ALS and FTD generative conditions, including Parkinson’s,
acts with and potentially alters the described as we age, and this is indeed the case. Huntington’s and Alzheimer’s diseases.
course of pathogenesis. Figure 1 attempts to A second way in which context could work
capture the authors’ main points, as well as this to enhance the R-loop and DPR story is in COMPETING FINANCIAL INTERESTS
cellular context. The G4C2 expansion leads to regard to DNA repair. Any somatic event that The authors declare no competing financial interests.
R-loop formation and DNA damage, as well leads to a loss of ATM, for example, would 1. McKinnon, P.J. Nat. Neurosci. 16, 1523–1529 (2013).
as to dipeptide RAN synthesis and inhibition increase the sensitivity of cells to downstream 2. Walker, C. et al. Nat. Neurosci. 20, 1225–1235
(2017).
of DNA repair. These two pathways, acting events requiring its activity. Compromised 3. Flores, B.N. et al. PLoS One 11, e0165084 (2016).
together, are sufficient to trigger neurodegen- ATM activity has been shown to increase 4. Zhang, Y.J. et al. Acta Neuropathol. 128, 505–524
eration, but both can be worsened by other with age. Indeed, the loss of ATM activity (2014).
5. May, S. et al. Acta Neuropathol. 128, 485–503
events taking place in the cell. Consider, for can occur on a neuron-by-neuron basis dur- (2014).
example, the creation of DNA damage by ing neurodegenerative disease15. If a neuron 6. Li, J. et al. Nat. Neurosci. 16, 1745–1753 (2013).
7. Goodarzi, A.A., Noon, A.T. & Jeggo, P.A. Biochem. Soc.
R-loops. Cells are constantly subjected to DNA begins with a deficit of ATM activity, the Trans. 37, 569–576 (2009).
damage and so have evolved overlapping layers effects of enhanced G4C2 production would 8. Aoki, Y. et al. Brain 140, 887–897 (2017).
of repair processes. Despite these restorative be amplified and thus hasten the cell along the 9. Boeynaems, S. et al. Mol. Cell 65, 1044–1055.e5
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

(2017).
efforts, unrepaired DNA damage accumulates road to destruction. 10. Schmidt, M.H. & Pearson, C.E. DNA Repair (Amst.)
and likely serves as a master driver of the aging The study by Walker et al.2 thus answers 38, 117–126 (2016).
process in neurons12 and other cells13 of the many questions but raises many others, as any 11. Kobayashi, H. et al. Am. J. Hum. Genet. 89, 121–130
(2011).
brain. Indeed, neuronal activity itself has been good paper should. The interdependent path- 12. Chow, H.M. & Herrup, K. Nat. Rev. Neurosci. 16,
proposed to contribute to DNA double-strand ways described in detail by the authors offer a 672–684 (2015).
13. Tse, K.H. & Herrup, K. Mech. Ageing Dev. 161 Pt A,
breaks14. We may be able to fix our breaks compelling model that accounts for many of 37–50 (2017).
when we are young, but as DNA damage accu- the known features of C9orf72-repeat-driven 14. Suberbielle, E. et al. Nat. Neurosci. 16, 613–621
mulates with age (at this locus and others), we disease. More importantly, in describing a (2013).
15. Shen, X., Chen, J., Li, J., Kofler, J. & Herrup, K. eNeuro
are less and less able to correct the errors. This molecular pathway at work in two uncommon https://dx.doi.org/10.1523/ENEURO.0124-15.2016
makes our brain cells increasingly vulnerable diseases, they potentially pull back the curtains (2016).

Jamais vu all over again

Rebecca D Burwell & Victoria L Templer
What is the basis for the feeling that someplace or someone is familiar? Molas et al. have identified brain structures involved
in signaling familiarity, a necessary element for the expression of preference for novelty.

Most of us have had the experience of the objective realization that they have indeed originally developed by Fantz5, has been
encountering a person who looks familiar, been previously experienced2. Both déjà vu and used to study cognition in nonverbal sub-
yet we cannot recall having met. A related jamais vu occur in temporal lobe epilepsy3, as jects including chicks, rodents, nonhuman
phenomenon is déjà vu, a vivid but inaccurate well as in normal individuals under ordinary primates and infant humans.
feeling that the current situation is familiar. situations. Compared with déjà vu, jamais vu Molas et al. employed two versions of the
This strong sense of familiarity occurs in is less common in normal populations and classic novelty task. The first is a social interac-
the absence of any explicit evidence that the much more prevalent in some neuropsychiatric tion test in which a mouse is first allowed to
situation was previously encountered. Déjà vu conditions; this difference in prevalence explore an empty pen and a pen holding an
is generally accepted to be a memory-based suggests that novelty and familiarity may be unfamiliar (or novel) juvenile demonstrator
illusion resulting from a brief bout of anomalous signaled by different brain pathways. mouse (Fig. 1a, left). In the test phase, the sub-
activity in memory-related structures Molas et al.4 provide evidence explaining ject mouse is presented with the now-familiar
of the medial temporal lobe1. Jamais vu, how we differentiate the new and strange demonstrator mouse and a novel demonstrator
sometimes regarded as the opposite of déjà vu, from the old and familiar. They have identi- mouse. Normal mice will explore the demon-
is the intense feeling that the current fied a circuit in the midbrain that combines strator mouse in preference to the empty pen
circumstances are novel and strange, despite familiarity and novelty signals to allow the and the novel demonstrator mouse in prefer-
expression of novelty preference, a capacity ence to the familiar demonstrator mouse. The
Rebecca D. Burwell is in the Department of Cognitive, exhibited by virtually all mammals that have second version of the novelty task is spontane-
Linguistic and Psychological Sciences, Brown been tested. Novelty preference and prefer- ous object recognition (Fig. 1a, right). Here the
University, Providence, Rhode Island, USA, and ential exploration of novelty have yielded a mouse is presented with two identical objects
Victoria L. Templer is in the Department of Psychology, number of tasks useful in the study of atten- in the study phase. In the test phase, the mouse
Providence College, Providence, Rhode Island, USA. tion, perception, recognition, sociability and is presented with a third copy of the familiar
e-mail: rebecca_burwell@brown.edu cognitive development. The novelty task, object along with a novel object. Normal mice

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 news and views

will preferentially explore the novel object, the mice, yellow light was delivered to halor- stimuli: photostimulation of the inhibitory
demonstrating novelty preference. hodopsin-expressing IPN interneurons to sup- IPN cells decreased subjects’ exploration of
Social and nonsocial recognition memory, press their activity (Fig. 1e, left). The other half novel objects. Thus, when IPN interneurons
as identified by the novelty task, rely on medial of the mice served as controls and received no are suppressed, overall IPN activity increases
temporal lobe structures6–10, but processing light. As expected, control mice explored the and exploration of familiarity increases.
information about novelty is also impor- novel mouse much more than the familiar one. When IPN interneurons are activated, overall
tant for non-mnemonic cognitive functions. In contrast, the light-exposed mice explored activity decreases and permits exploration of
Dopaminergic areas in the midbrain, includ- the familiar mouse just as much as the novel novel stimuli. The authors suggest that IPN
ing the ventral tegmental area (VTA), are one (Fig. 1e, right). interneurons act as a brake on the exploration
known to encode novelty11, but how novel Next, the authors expressed channelrho- of familiar stimuli, allowing the expression of
items become familiar is not known. To dopsin-2, a blue-light-activated cation chan- novelty preference.
address the issue of where familiarity signals nel, in IPN inhibitory interneurons. Activation Finally, Molas et al. used optogenetic tools
emerge in the mammalian brain, the authors of interneurons should have had the effect to modulate excitatory input to the IPN aris-
took a hint from zebrafish experiments in of decreasing overall IPN activity (Fig. 1f, ing from the mHB and the VTA. These inputs
which social conflict resolution was found to left). Photostimulation of the inhibitory were hypothesized to provide familiarity
rely on medial habenula (mHB) input to the IPN cells decreased subjects’ exploration of and novelty signals to the IPN, respectively
interpeduncular nucleus (IPN)12. Molas et al. novel mice without changing exploration of (Fig. 1d). Photosuppression of the mHB ter-
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

thought that the IPN and its input from mHB familiar mice (Fig. 1f, right). Tests with inan- minals in the IPN increased exploration of
might be involved in signaling familiarity. imate objects paralleled results with social familiar social and nonsocial stimuli without
The authors began by testing mice in a ver-
sion of the novelty task that involves social a Study Test Study Test
interaction (Fig. 1a, left). A subject mouse
would actively investigate a novel demonstra-
tor mouse, and investigation diminished as the
demonstrator mouse became more familiar.
When a second novel demonstrator mouse was
presented, the subject mice showed rebound b Day 1: novel Day 3: familiar Day 4: familiar Day 5: familiar Day 7: familiar
of social investigation. If the IPN is involved
in signaling familiarity, then social familiar-
ity should activate the IPN. Using expression
of the immediate-early gene c-Fos as a proxy
for neuronal activation, the authors found
that IPN activation was much higher upon IPN c-Fos
activity
exposure to a familiar demonstrator mouse
than upon exposure to a novel demonstrator
mouse. The same results were observed with
c d IPN GABA Familiar
exposure to familiar objects (Fig. 1a, right). Output
IPN EXC mHB
The authors next asked whether IPN activ- mHB

ity increased with the degree of familiarity. VTA DA

Subject mice were exposed to the same dem- VTA
IPN
onstrator mouse once a day for up to 7 days. mHB EXC VTA
Novel
c-Fos increased progressively with successive IPN
encounters, peaking on the fifth day of expo-
sure (Fig. 1b). e f
– – + + +
Interestingly, c-Fos was evident in IPN
cells containing the neurotransmitter GABA.
This suggests that IPN cells involved in signal-
ing familiarity are largely inhibitory GABAergic Figure 1 A circuit-based mechanism for familiarity signaling and novelty preference. (a) Mammals
interneurons (Fig. 1c,d). The authors hypoth- show a preference for novelty. A mouse will explore an unfamiliar mouse more than a familiar mouse
esized that the IPN inhibitory interneurons act (left) and a novel object more than a familiar object (right). (b) Following repeated exposures to
as a brake for novelty-induced exploration. the same mouse, shown left to right, c-Fos activity in the IPN increases as compared to activity
following exposure to a novel mouse, peaking at the fifth exposure to the same mouse. (c) This
To test this, they used optogenetics, express- sagittal schematic of the mouse brain shows the location of the interpeduncular nucleus (IPN)
ing a yellow-light-activated chloride pump, together with two important input regions, the medial habenula (mHB) and the ventral tegmental
halorhodopsin, in the GABAergic interneu- area (VTA). (d) These regions form a circuit for familiarity signaling and expression of novelty
rons of the IPN to enable optical suppression preference in which the IPN is a critical node. Cholinergic or glutamatergic input from the mHB
of the cells’ activity. Suppression of interneu- provides a familiarity signal, and dopaminergic input from the VTA provides a novelty signal.
rons would be expected to increase overall (e) Optical suppression of IPN interneurons or mHB input to the IPN boosts the familiarity signal,
increasing exploration of a familiar stimulus with no impact on exploration of a novel one. Optical
IPN activity. Mice explored the demonstrator
activation of VTA input to the IPN also increases exploration of a familiar stimulus, presumably by
mouse for two consecutive days. On the third mimicking novelty. (f) Optical activation of IPN interneurons or mHB input to IPN degrades the
day, they were offered the choice between the familiarity signal, decreasing exploration of a novel stimulus with no impact on exploration of a
familiar mouse and a novel mouse. For half familiar one. DA, dopamine; EXC, excitatory; GABA, GABAergic.

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 news and views

affecting exploration of novel stimuli activated the entorhinal-to-hippocampal déjà vu and jamais vu contribute differently
(Fig. 1e, center left). Photostimulation of the field CA1 pathway, also known as the tem- to symptom profiles of neuropsychiatric
mHB terminals in the IPN decreased explora- poro-ammonic pathway13. When rats were disorders. More importantly, the findings of
tion of novel social and nonsocial stimuli with- presented with novel objects, perirhinal cor- Molas et al. have profound implications for
out affecting exploration of familiar stimuli tex activated the entorhinal-to-dentate gyrus understanding and treating neuropsychiatric
(Fig. 1f, center and right). Next, the authors pathway, also known as the perforant pathway. disorders in which processing of novelty and
photostimulated the VTA dopaminergic ter- Another c-Fos study showed that exploration familiarity are compromised.
minals in the IPN. As in the phenomenon of of a novel environment increased activation
jamais vu, this manipulation mimicked the in the hippocampus, the prelimbic prefrontal COMPETING FINANCIAL INTERESTS
novelty signal, resulting in increased explo- cortex and the dopaminergic reward circuit14. The authors declare no competing financial interests.
ration of a familiar mouse (Fig. 1e, center Exploration of a familiar environment, how-
right). Interestingly, the photostimulation of ever, increased activation in the amygdala. A 1. O’Connor, A.R. & Moulin, C.J.A. Curr. Psychiatry Rep.
12, 165–173 (2010).
dopamine terminals did not affect exploration better understanding of how the midbrain cir- 2. Ellis, H.D., Luauté, J.P. & Retterstøl, N.
of inanimate objects. Thus, the novelty signal- cuits interact with the forebrain circuits could Psychopathology 27, 117–120 (1994).
3. Sengoku, A., Toichi, M. & Murai, T. Psychiatry Clin.
ing pathway may differ for social and nonso- help explain the human prevalence differences Neurosci. 51, 23–26 (1997).
cial signals. The authors suggest that different between déjà vu and jamais vu. Future work 4. Molas, S. et al. Nat. Neurosci. 20, 1260–1268 (2017).
subtypes of VTA dopaminergic neurons may could elucidate other neural bases of neuro­ 5. Fantz, R.L. Science 146, 668–670 (1964).
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

6. Feinberg, L.M., Allen, T.A., Ly, D. & Fortin, N.J.

mediate novelty responses to social and non- psychiatric disorders by explaining dysregu- Neurobiol. Learn. Mem. 97, 7–16 (2012).
social stimuli. lation of novelty and familiarity processing, 7. Ho, J.W. et al. J. Neurosci. 35, 13323–13335
It is tempting to conclude that novelty is depersonalization, derealization and other (2015).
8. Kogan, J.H., Frankland, P.W. & Silva, A.J. Hippocampus
simply the absence of memory-based famil- symptoms that involve detachment from 10, 47–56 (2000).
iarity. Yet a number of studies have provided familiar surroundings. 9. Heimer-McGinn, V.R., Poeta, D.L., Aghi, K., Udawatta, M.
& Burwell, R.D. J. Neurosci. 37, 4819–4829
evidence that the processing of novelty In this elegant series of experiments, Molas (2017).
information and familiarity information can et al. have elucidated the mechanisms and cir- 10. Templer, V.L. & Hampton, R.R. Curr. Biol. 23,
be functionally dissociated in the forebrain cuitry by which novelty transitions to familiar- R801–R806 (2013).
11. Bunzeck, N. & Düzel, E. Neuron 51, 369–379
medial temporal lobe memory system. A ity. A primary contribution of their work is (2006).
study using c-Fos expression methods com- the demonstration that novelty and familiar- 12. Chou, M.Y. et al. Science 352, 87–90 (2016).
bined with structural equation modeling ity are signaled by different pathways, partially 13. Albasser, M.M., Poirier, G.L. & Aggleton, J.P. Eur. J.
Neurosci. 31, 134–147 (2010).
found evidence that, in rats presented with overlapping in the IPN, to support novelty 14. Bourgeois, J.P. et al. Cereb. Cortex 22, 1007–1015
familiar objects, caudal perirhinal cortex preference. These findings may explain why (2012).

Is population activity more than the sum of its parts?

Jonathan W Pillow & Mikio C Aoi
A study introduces innovative ways to test whether neural population activity exhibits structure above and beyond that of its
basic components.

Suppose a fancy new analysis method reveals an and Cunningham propose new methods for peri­stimulus time histograms, or time-varying
(apparently) surprising form of population-level resolving this question1. firing rates, from multiple neurons across time
organization in your large-scale neural data set. Their main contribution is to formalize the and across multiple experimental conditions.
How can you tell if the observed pattern is truly notion of primary (or already known) fea- We can think of these data as living in a 3D
surprising? Is it the hallmark of a population- tures of a neural population so that claims of tensor (or array) with axes denoting time, neu-
level mechanism that reveals the circuit’s true surprising population structure can be tested ron and condition (Fig. 1). Every entry in the
function, or is it merely an expected byproduct against them. To make this concrete, consider, tensor is a number indicating the firing rate of
of things we already knew about neurons for example, the recent claim that a neural a particular neuron at a single time bin for a
contained in the population? To put it bluntly: population exhibits ‘rotational dynamics’2, a particular condition.
when are findings of population-level structure contention we’ll return to later. Elsayed and What would it mean for this dataset to con-
‘new science’ and when are they merely old Cunningham show that standard shuffling tain meaningful population structure above
knowledge dressed up in new clothes? In this methods do not, in fact, preserve the full and beyond its primary features? Elsayed and
month’s issue of Nature Neuroscience, Elsayed set of primary features of a neural popula- Cunningham propose that we should consider
tion; to address this problem, they introduce as primary the means and correlations along
Jonathan W. Pillow and Mikio C. Aoi are in the two methods for sampling from a properly each side of the tensor: temporal correlations,
Princeton Neuroscience Institute and Department defined null model, allowing claims of novel neuronal correlations and conditional corre-
of Psychology, Princeton University, Princeton, population-level structure to be put to the lations. Temporal correlations reflect the fact
New Jersey, USA. appropriate test. that, before we say anything about population-
e-mail: pillow@princeton.edu or The starting point for the population- level structure, neural firing rates are typically
maoi@princeton.edu level analyses in question is a collection of smooth in time. Neuronal correlations, the

1196 volume 20 | number 9 | SEPTEMBER 2017 nature neuroscience