# Talk:Up and down states

## Reviewer A

Very nice overview - I have a couple of suggestions of related work that could be cited for completeness:

• First, Contreras and Steriade (2005) performed dual (simultaneous) intracellular recordings between thalamic and cortical neurons in anatomically-related areas, and showed very well the phase relations between Up/Down states. Like Cortex-Basal Ganglia relations, the Up/Down transitions are synchronous between thalamus and cortex.

-- I added this reference - CJW

• Second, the review should mention more explicitly that Up/Down states are relatively easy to observe in cortical slices. Sanchez-Vives and McCormick (2000) showed Up/Down states in ferret V1 slices, if the slice is excited by increasing extracellular potassium concentration. These Up/Downs have very similar characteristics as those seen during anesthesia (except for longer down states). Yuste's group (Cossart et al., Nature 2003) also demonstrated Up/Down states in mouse cortical slices, but with somewhat different characteristics (more reminiscent of persistent activity states).

-- Good point. I added mention of up and down states in slices, slabs and slice cultures - CJW

• Third, Hughes et al. (Neuron, 2002) have found that slow oscillations with similar Up/Down dynamics as thalamic recordings in vivo can be generated intrinsically by thalamic relay cells, but only if metabotropic receptors are stimulated. This could also participate to the large-scale synchrony of Up/Downs in vivo, and probably worth to be mentioned as well.

-- I added this reference- CJW

• Finally, Rudolph et al. (J Neurosci, 2007) have made a conductance analysis of Up and Down states in naturally sleeping cats. This analysis showed an increased conductance during the Up state (compared to the Down state), in agreement with previous measurements in anesthetized cats (Contreras et al., J Physiol 1996), but in contrast with measurements in anesthetized rats (Waters and Helmchen, 2006). Rudolph et al.also gave evidence for strong inhibitory conductances during the Up state (spikes seem more correlated with inhibitory conductances than with excitatory conductances). This would also be useful to be pointed to the reader (especially those interested in the relation between Up/Down states and information processing).

## Reviewer C

This is an outstanding article made by an eminent specialist of the field. This paper is clearly written and adequately illustrated and would be of great help for confirmed neuroscientists but also for a large audience interested by the brain dynamics and their cellular counterpart. The author uses the cerebral cortex and the striatum to illustrate and discuss the up-and-down activities. The membrane and synaptic mechanisms underlying the two-state membrane potential in these two structures have been extensively studied, in particular by the author himself. I have no major criticisms. However, if the paper can be increased in length, I think that some additional information could be provided in order to extend the functional relevance of up-and-down activities and their possible cellular mechanisms.

1. Concerning the cellular mechanisms responsible for the expression of up-and-down states, it might be interesting to mention some works demonstrating that such two-state behavior can be produced by “pure” intrinsic mechanisms due to specific voltage-gated ion channels. For instance, cerebellar Purkinje cells in vivo show bistability of membrane potential and spike output on the time scale of seconds. The transition between membrane potential states can be bidirectionally triggered by the same brief current pulses, demonstrating the intrinsic nature of Purkinje cell bistability (Loewenstein et al., Nat Neurosci. 2005, 8(2):202-11).

-- I have inserted this reference in the section on bistability. -- CJW

2. As mentioned in the article, up-and-down states found in cortical and striatal neurones are correlated with cortical slow waves, which occur during anaesthesia or specific states of consciousness, such as slow wave sleep (see the references cited in the article, Steriade et al, Timofeev et al, Mahon et al, Kazanetz et al). These well recognized findings, which provide a correlative and causal link between global brain dynamics and single cell activity, could be illustrated by simultaneous recordings from cellular up-and-down and EEG recordings. This is an important point relative to the functional relevance of up-and-down states, and more specifically with the states of vigilance.

--This is an interesting point. I certainly agree with this statement, if it is a statement about the slow oscillations. But things are less clear for the cellular properties responsible for up and down states (which of course participate in the slow oscillations).- CJW

3. Finally, another important issue could be developed: the differential integrative properties of central neurones in response to natural sensory stimuli during the two membrane states. As shown by Peterson and colleagues (Petersen et al, Proc Natl Acad Sci U S A. 2003;100(23):13638-43), sensory-evoked synaptic responses in primary somatosensory cortical neurones during spontaneous up states were smaller and briefer compared to those evoked from the down state. Surprisingly, whisker deflections evoked fewer action potentials during the spontaneous depolarizations despite neurons being closer to threshold. A similar finding has been obtained by the author of the present article (Sachdev et al, J Neurophysiol. 2004;92(6):3511-21). As another example of information processing during up-and-down states, in the cerebellum, natural sensory stimuli activating climbing fiber input can switch Purkinje cells between the two states, suggesting that Purkinje cell up-and-down states may have a key role in the short-term processing and storage of sensory information in the cerebellar cortex. (Loewenstein et al., Nat Neurosci. 2005, 8(2):202-11).

-- Of course, I also think that this is important. However, I can't summarize this literature in the space available. This should have a page of its own.- CJW

Nice article. Very informative. One thing:
"the I-V curve slope (the input resistance) decreases with hyperpolarization"
Shouldn't the I-V curve slope be the inverse of input resistance? Floorsheim 22:55, 27 February 2008 (EST)

-- Yes, I fixed this - CJW

## Reviewer B

Excellent article.

I have very few comments that I believe will improve this review.

1. I introduced minor changes to the text. This concerns manly typos or some precisions.

2. It should be stressed that during natural states of vigilance UP and DOWN states these states are found in cortical (Steriade et al., 2001) and striatal (Mahon et al., 2006) neurons during slow-wave sleep only.

-- I rephrased this to emphasize the point - CJW

3. I didn’t understand sentence “These properties continue to influence cellular activity in other circumstances not associated with slow oscillations (Mahon et al., 2006; Destexhe et al. 2007).” In both studies UP and DOWn states were recorded during slow-wave sleep.

-- Also rephrased. This had to do with the distinction I am making between slow oscillations and up and down states. - CJW

4. It could be mentioned that cortical interneurons and reticular thalamic neurons also show UP and Down states. At least some reticular thalamic neurons reveal intrinsic bistability (Fuentealba et al., 2005).

-- added a reference on thalamic bistability  from another reviewer - CJW


5. Legends should be more explicit.

-- Added legends - CJW 6. GHK needs to be spelled out. -- Did this - CJW

7. It would be important to show I-V curves for UP and Down states referenced in chapter Ionic mechanisms…

Fuentealba P, Timofeev I, Bazhenov M, Sejnowski TJ, Steriade M (2005) Membrane bistability in thalamic reticular neurons during spindle oscillations. J Neurophysiol 93:294-304.

Mahon S, Vautrelle N, Pezard L, Slaght SJ, Deniau J-M, Chouvet G, Charpier S (2006) Distinct patterns of striatal medium spiny neuron activity during the natural sleep-wake cycle. J Neurosci 26:12587-12595.

Steriade M, Timofeev I, Grenier F (2001) Natural waking and sleep states: a view from inside neocortical neurons. J Neurophysiol 85:1969-1985.