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Next, animals were intubated per the oral cavity, fixed in a stereotaxic device Kopf , and ventilated with oxygen and isoflurane 0. Vital signs, including heart rate, blood oxygen, end-tidal carbon dioxide, and respiratory rate were continuously monitored Surgivet. Eye ointment was applied to prevent corneal drying. A bolus of bupivacaine was injected subcutaneously before making an incision to expose the cranium.

The skin was retracted, fascia was cleared, and a ground screw was placed in the skull behind lambda. Craniotomies were drilled to insert injection pipettes into the claustrum 1. Location and extents of each brain region were based on the rat atlas and compared to subsequent analysis of Nissl stained alternate sections Paxinos and Watson After tracer injections, the incision was sutured, the wound was treated with antibiotic ointment, and the rats were returned to their home cage for 7—10 days to allow for tracer transport.

Histological sections were acquired after the olfactory bulbs, cerebellum, and brainstem were removed. A slit was made into one hemisphere to denote the correct side while mounting. The first series was mounted and stained with thionin to reveal cytoarchitecture. The second series was processed for the presence of BDA as described previously Smith et al. Briefly, sections were rinsed in 0. Sections were rinsed twice in 0. The reaction was stopped by two washes in 0.

Sections were mounted, air dried, dehydrated in ethanol, defatted in xylene, and coverslipped with Cytoseal. The third series was processed for fluorescent labeling by simply mounting, dehydrating, defatting and coverslipping. Digital reconstructions of the labeling patterns were created by plotting labeled cells and terminals relative to cytoarchitectural boundaries.

Higher magnification images were acquired with a confocal microscope Olympus Fluoview , allowing us to show FR-labeled terminals nm excitation, — nm detection intermingled with FG-labeled neurons nm excitation, — nm detection. Digital reconstructions of tracer labeling were analyzed using MDPlot software version 5. Consistent with the fact that Gng2 protein is localized in the claustrum at rostrocaudal coordinates that also contain the striatum, we plotted labeled cells and terminals in those sections where the striatum was present Mathur et al.

Overlap bins were defined as containing a minimum of four FR-labeled terminals and one FG-labeled neuron. Total overlap was then expressed as a percentage of total number of labeled bins. Statistical analyses were performed with Origin software version 8. To investigate the functional connectivity of the claustrum, we performed RS-fMRI on awake rats trained to remain quiescent while restrained during functional imaging Liang et al.

Seed-based correlational analysis was used on a voxel-by-voxel basis, and the locations of the claustral seeds are presented in structural MRIs in Figure 1. We characterized the whole-brain functional connectivity of the claustrum in both the awake and isoflurane-induced, deeply anesthetized states as shown in Figure 2. For claustrum seeds, the voxels immediately ventral and lateral to the external capsule were used, at rostrocaudal levels containing the neostriatum as previously described Mathur et al RS-fMRI in the awake state reveals bilateral functional connections of the claustrum that are lost during anesthesia.

Strong functional connectivity was observed bilaterally between the claustrum, mediodorsal thalamus MD , medial prefrontal cortex mPFC , and several other cortical areas including retrosplenial, sensorimotor and multimodal regions. The claustrum also displayed functional connectivity with the contralateral claustrum. White boxes correspond to sections shown in tracing data. Color bar represents correlation coefficients and applies to panel b as well. In the awake state Fig. In addition, the claustrum is functionally connected with the medial prefrontal cortex mPFC , the surrounding cortical areas i.

We also observed strong functional connections with the contralateral claustrum, even though no rodent studies have ever reported that the claustrum has direct anatomical connections with its counterpart in the contralateral hemisphere. Furthermore, RS-fMRI analysis in the awake state indicates that the claustrum has moderately-strong functional connections with the mediodorsal MD thalamus and widespread parts of sensory and association cortex. Administration of isoflurane produced significant changes in the claustrum-based functional network compared to the awake state.

Specifically, as shown by Figure 2 , functional connections of the claustrum with mPFC and MD-thalamus were markedly decreased in the deeply anesthetized state. By contrast, the functional connections of the claustrum with the cingulate and agranular motor cortex, as well as with the contralateral claustrum, appeared unchanged no significant differences in the anesthetized state. Qualitatively similar results were obtained in both hemispheres regardless of whether the unilateral seed was placed in the left or right claustrum data not shown. Collectively, these results indicate that the anesthesia-induced changes in claustrum connectivity are linked to specific brain regions.

Statistical analysis comparing claustrum seed in the awake and anesthetized states. Positive t-values indicate pixels where functional connections were stronger in the awake state compared to the deeply anesthetized state. To verify the specificity of our claustrum seed for revealing claustrum-related networks, we also placed seeds in the adjacent insular cortex, which is located just lateral to the claustrum. In the awake state, the unilateral insular cortex seed Fig. The insular functional maps showed little resemblance to the claustrum-based network, and this indicates that the changes in the connectivity maps of the claustrum do not represent changes in blood flow to this nearby region.

Resting state functional network of insular cortex and striatum are different from the claustrum. Grey arrows indicate regions of high correlation with the claustrum that show no correlation with insula. Grey arrows indicate regions of high correlation with the claustrum. White pixels represent seed region.

The Claustrum Structural, Functional, and Clinical Neuroscience

Color bar represents correlation coefficients. An additional control experiment was performed using a seed based analysis of the striatum that lies medially adjacent to the claustrum Fig. This analysis revealed bilateral, functional connections with mPFC, cingulate, and agranular motor cortex, as well as with MD thalamus, which were very similar to our claustrum seed analysis.

However, our striatum seed analysis did not show strong connections with other widespread regions of sensory cortex that were observed in our claustrum seed analysis. The functional connections observed in our striatum seed match known inputs to this region of striatum, including bilateral inputs from cingulate cortex Smith and Alloway , agranular motor cortex Alloway et al. In support of our claustrum seed analysis, each of these cortical regions also sends bilateral projections to claustrum in addition to their striatal projections.

Furthermore, MD thalamus is known to project to both claustrum and striatum Bay and Cadvar Finally, sensory cortical projections to striatum are known to terminate in more dorsolateral and caudal regions of striatum Hoover et al. Our control seed analyses of adjacent insular cortex and striatum compared to the claustral seed thus show three different networks of functional connectivity.

This suggests that our analyses are highly specific to the brain regions contained within a seed and represent their unique functional networks. To determine how the functional connectivity of the claustrum relates to its anatomical connections, we compared the RS-fMRI data with the labeled connections revealed by conventional neuronal tracing.

This aim was partly motivated by the fact that direct interhemispheric claustroclaustral connections were suggested by DTI data in humans Milardi et al. To our knowledge, no study has injected the claustrum with an anterograde tracer in rats. Therefore, we injected the anterograde tracer, biotinylated dextran amine BDA , into the claustrum of one hemisphere.

Although some of the injected tracer diffused into the surrounding insular cortex, most of it occupied the claustrum Fig. These anterograde tracer deposits revealed a few labeled fibers in the contralateral insular cortex but not in contralateral claustrum Fig. Hence, the functional claustroclaustral connectivity observed in both awake and anesthetized rats cannot be mediated by direct, monosynaptic connections Fig.

Instead, the correlated BOLD signals in the claustrum of both hemispheres must be due to relatively strong multi-synaptic connections between the claustrum and the agranular cortex Smith and Alloway , ; Smith et al. Our tracing data revealed claustral projections to the MD-thalamus in both hemispheres, but the ipsilateral connections were much denser Figure 2f.

These bilateral anatomical connections provide a substrate for mediating the bilateral functional connections of the claustrum with the MD nuclei in the awake state. Despite these moderately-strong monosynaptic anatomical projections, functional connectivity between the claustrum and MD-thalamus was noticeably reduced in the anesthetized state. This finding demonstrates that monosynaptic anatomical connections between the claustrum and MD thalamus have functional connections in the awake state that are significantly lessened in the deeply anesthetized state.

The Claustrum

In contrast to the bilateral projections to MD thalamus, most of the labeled projections from the claustrum terminated in ipsilateral cortical areas. This corroborates previous tracing studies conducted on multiple species Crick and Koch ; Edelstein and Denaro ; Goll et al. High resolution images of these claustrocortical projection terminals revealed thin fibers Fig.

This type of presynaptic morphology was also observed in claustrocortical projections that contact dendritic spines of excitatory cells in cat visual cortex da Costa et al. As indicated by the structural MRIs in Figure 1 , we also examined claustral connectivity after placing a unilateral seed in prelimbic cortex, which is a subdivision of rodent mPFC Hoover and Vertes This part of mPFC was chosen because it showed the greatest change between the awake and anesthetized states in our claustrum-seed analysis Figs.

In the awake state, the mPFC has strong functional connections with the claustrum and MD nuclei in both hemispheres Fig. Consistent with our claustrum seed analysis, isoflurane-induced, deep anesthesia caused significant changes in the functional network of the mPFC Fig. Voxel by voxel statistical comparison of the connectivity maps generated by mPFC seeds in the awake and the anesthetized states are shown in Fig.

These data are consistent with the results obtained when the seed was placed in the claustrum. Bilateral functional connectivity was observed between mPFC and the claustrum, mediodorsal thalamus MD , and retrosplenial and entorhinal cortices.


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Anterogradely-labeled terminals were also observed in contralateral MD, terminating around retrogradely-labeled neurons, demonstrating an interhemispheric cortico-thalamo-cortical loop. Overlapping bins white contained at least 4 FR-labeled terminals and 1 FG-labeled neuron. Abbreviations: cc, corpus callosum; ec, external capsule; lv, lateral ventricle; ac, anterior commissure.

Statistical analysis comparing mPFC seed in the awake and anesthetized states. Pink arrows point to significant positive t-values for MD-thalamus and claustrum. In parallel with the RS-fMRI analysis of mPFC, we characterized the anatomical projections of mPFC by injecting this region with an anterograde tracer in one hemisphere and a retrograde tracer in the other hemisphere of the same animal Fig.

This revealed an interhemispheric cortico-thalamo-cortical circuit Fig. These separate deposits of anterograde and retrograde tracers in mPFC of opposite hemispheres revealed a strong interhemispheric circuit that involved the claustrum Fig. While most anterogradely-labeled projections from mPFC terminate in the contralateral claustrum, the retrogradely-labeled claustral neurons were located almost exclusively in the ipsilateral hemisphere. To quantify this relationship, we plotted the labeled neurons and terminals Fig. Hemispheric differences in tracer labeling were significant Fig.

Consequently, there was significantly more terminal-neuronal overlap in the claustrum of the hemisphere that received the retrograde tracer injection Fig. Quantification of tracer labeling from mPFC injections. Solid lines represent means, shaded regions denote standard error of the mean SEM. Error bars show SEM. The interhemispheric functional connectivity of the claustrum was also confirmed by partial correlation analysis Fig.

By removing correlations involving frontal cortex including AGm, Cg, and PrL in a unilateral claustrum-based seed analysis, the claustroclaustral correlations were noticeably attenuated see pink arrows in Fig. This manipulation suggests that the claustroclaustral functional connectivity observed in both the awake and anesthetized states is mediated by strong disynaptic connections through regions of frontal cortex that are not affected by anesthesia mainly AGm and Cg.

Partial correlation analysis shows loss of functional connectivity with contralateral claustrum after removal of mPFC correlations. White arrows indicate regions of mPFC with removed correlations. Pink arrows identify MD and contralateral claustrum. Placement of a unilateral seed in nucleus MD see Fig. During isoflurane-induced, deep anesthesia, however, the functional connections of the MD nucleus with both the claustrum and mPFC were markedly reduced Fig. These data corroborate the diminished functional connections observed in our claustrum- and mPFC-seed analyses.

As observed with our claustrum seed analysis, isoflurane anesthesia caused significant changes in the functional network of MD thalamus. Voxel by voxel statistical comparison of our MD seed analysis between the awake and the anesthetized states are shown in Fig. During anesthesia, functional connectivity between MD thalamus and claustrum, as well as mPFC, was significantly attenuated see pink arrows in Fig. These results confirm anesthesia induced functional connectivity changes observed using claustrum and mPFC seed based analyses.

RS-fMRI analysis in the awake state reveals functional connections with the MD thalamus that are lost during anesthesia. Scale bars: 1mm in c , d , e. Abbreviations: AM, anteromedial nucleus; VL, ventrolateral nucleus; LV, lateral ventricle; cc, corpus callosum; ec, external capsule; ns, neostriatum; ac, anterior commissure.

Statistical analysis comparing MD seed in the awake and anesthetized states. Pink arrows point to significant positive t-values for claustrum and mPFC. We also made large tracer injections in nucleus MD Fig. Similarly, both anterograde and retrograde labeling were observed in the claustrum following tracer injections into MD, thereby indicating reciprocal connectivity, which has been previously observed in both rodents Bay and Cadvar ; Mitchell and primates Erickson et al.

The anterogradely-labeled thalamoclaustral fibers were thin with drumstick shaped, terminals indicative of modulator type synapses Crick and Koch ; Sherman and Guillery , also observed for the claustrocortical projections Fig. The anatomical connectivity of the claustrum is illustrated by a circuit diagram in Figure Line widths depict connection strengths based on our neuronal tracing data. Together, neuronal tracing and resting-state functional connectivity demonstrate that the claustrum is involved in the bilateral coordination of many cortical areas.

Furthermore, despite lacking a direct anatomical connection, the claustrum is functionally connected to the claustrum in the opposite hemisphere, likely via interhemispheric circuits involving mPFC, cingulate, and agranular motor cortex. Our seed-based RS-fMRI analysis indicates that the claustrum has previously unknown bilateral functional connections with MD-thalamus and mPFC in the awake state, which were verified by anatomical tracing.

These claustral functional connections with mPFC and MD thalamus were significantly weakened in the isoflurane-induced, deeply anesthetized state. Finally, claustro-cortical and thalamo-claustral axonal terminals are thin and have modulator-type synaptic morphology. Circuit diagram of claustrum connectivity. Circuit diagram showing the connections of the claustrum based on the findings from this paper and cited references. Enclosed in the pink, dashed box are the brain regions shown by RS-fMRI to be lost in the transition from the awake to the anesthetized state. Line widths correspond to strength of anatomical connections.

Many investigators have hypothesized that the claustrum is responsible for binding multisensory information Crick and Koch ; Smythies et al. Most claustral studies have characterized the cytoarchitecture, neurochemical make-up, and anatomical connectivity of the claustrum for review Edelstein and Denaro ; Mathur ; Smythies et al.

Stimulation studies in cats have shown that the claustrum exerts a mix of excitatory and inhibitory effects on cortex reviewed in Sherk and neuronal recordings in the claustrum have revealed modality-specific responses to sensory stimulation LeVay and Sherk ; Olson and Graybiel ; Remedios et al. Though we did not perform electrophysiological recordings in the claustrum, our anatomical data suggest that claustro-cortical and thalamo-claustral transmission are mediated by modulator type synapses. This bouton morphology is associated with slow propagation due to thin axon diameter and small amplitude post-synaptic potentials that exhibit paired-pulse facilitation, which suggests that these connections modify activity in their target structures instead of transmitting high fidelity information with a strong, driving force Crick and Koch ; da Costa et al.

Our anatomical results beckon future electrophysiological studies to characterize the influence of claustral synapses on its targets, and suggests that the claustrum plays a role in modulating cortical activity, perhaps to alter cortical oscillations Smythies et al. Our study is the first to assess the whole-brain, functional network connectivity of the claustrum during the awake and anesthetized states.

Our results reveal claustral involvement in vast interhemispheric functional networks, in support of previous anatomical tracing studies Smith and Alloway , ; Smith et al b. Interestingly, we identify a functional connection between the claustra of each hemisphere that seems to be mediated by interhemispheric connections through the corpus callosum with mPFC, cingulate, and motor cortex. Furthermore, functional connectivity studies done in acallosal mice show a loss of interhemispheric functional connectivity between motor cortex and the region of the claustrum see Fig.

Together these data suggest a highly synchronized, interhemispheric circuit involving regions of frontal cortex and the claustrum, whose function as yet remains unknown. Insight into the function of these interhemispheric claustral circuits may emerge from comparative studies across species. However, in contradiction to the results in our current study in rodents, a recent anatomical tracing study from mPFC in marmosets observed that projections to the ipsilateral claustrum were much stronger than those in the contralateral claustrum Reser et al. Claustral connectivity with cortex varies across species, including across different primate lineages Sherk Our discovery of bilateral corticoclaustral connections in the rat prompted the view that the claustrum has a role in coordinating cortical areas that process sensorimotor information relevant to bilaterally-coordinated movements such as eye movements or exploratory whisking Alloway et al.

Analysis of the interhemispheric cortico-claustral projections from supplementary or frontal eye fields in primates would allow direct inter-species comparison of cortico-subcortical networks controlling homologous behaviors with the caveat that eye movements in rodents and primates are qualitatively different. With regard to interhemispheric functional circuitry, differences in the weighting of interhemispheric projections of mPFC between rodent and marmoset provides an opportunity for exploring the relationship between anatomical and functional networks, but requires future RS-fMRI experiments in marmosets.

Based on recent clinical evidence, the claustrum has been hypothesized to play a role in the networks underlying the conscious state Koubeissi et al. Our data show that the claustrum is functionally connected with mPFC and MD thalamus in the awake state, and these functional connections are significantly reduced during deep anesthesia even though other functional connections persist. These data pinpoint which claustral connections are functionally affected by isoflurane anesthesia, but allow only limited speculation on functional mechanisms.

One limitation is that we only investigated the awake and deeply anesthetized state, and not the transition period between these states, which may provide insight into the functional mechanism by which consciousness is lost during anesthesia. To ascertain the specificity of our seed based analysis to a region as small as the claustrum, we performed control seed-based analysis of regions directly medial striatum and lateral insular cortex to the claustrum.

We found that both claustrum and striatum have strong functional connections with AGm, Cg and PrL cortex, which is consistent with known anatomical data demonstrating that these cortical regions project to both the striatum and claustrum Alloway et al. This anatomical data is further supported by our mPFC seed analysis in the awake state, which shows strong connections to both claustrum and striatum see Figure 5a. Functional connectivity was observed between MD thalamus with both the claustrum and striatum, matching the anatomical connections revealed by our anterograde tracing experiments on the MD thalamus see Figure 9e, f.

However, our striatum seed analysis did not show strong connections with other widespread regions of sensory cortex, which were observed in our claustrum seed analysis, owing to striatal topography whereby sensory projections terminate in more dorsolateral and caudal regions Hoover et al. Seeds placed in the insular cortex, which lies directly adjacent to the claustrum revealed a functional network that differed substantially from the claustral functional network. The main hypotheses concerning the function of the claustrum have focused on neural mechanisms that mediate multisensory integration, salience detection, and attention.

Though we did not test the effects of sensory stimulation, our data show functional connectivity between the claustrum and widespread regions of sensory cortex in both hemispheres. This confirms anatomical studies showing that the claustrum is connected with all sensory areas, and provides evidence that the claustrum is involved in multisensory processing.

However whether these modalities are integrated at a single cell level within the claustrum remains contradictory Spector et al. Our data do not directly address the role of the claustrum in attention, but we detected strong functional connectivity between the claustrum and frontal cortical regions Cg, AGm that are believed to play a role in directed attention as part of their role in motor control Reep and Corwin ; Smith and Alloway ; Interestingly, we found the strongest functional connectivity of the claustrum with cortex was to these attention-related regions of frontal cortex, whereas weaker connections were observed with sensory cortex.

This further emphasizes the potential role of the claustrum in mechanisms of attention. When considered with our anatomical data that claustrocortical projections are modulator type synapses thought to feature paired-pulse facilitation , our data suggest that the claustrum may modulate attention through frontal cortex AGm, Cg, PrL. However, further studies are needed to directly test this hypothesis.

The use of anesthetics to study mechanisms of consciousness require understanding both the pharmacological effects of the drug on brain physiology, as well as the systems-level circuit changes that lead to a loss of consciousness.

The claustrum : structural, functional, and clinical neuroscience

In our experiments relatively high doses 1. As a result, the changes in functional connectivity observed here may differ from what would have been observed if lower or higher doses had been administered. Anesthesia is thought to have a dose dependent effect on functional connectivity Peltier et al. Moderate to high doses cause significant changes in functional connectivity compared to the awake state, whereas functional connectivity under lower doses of anesthesia have in some cases been shown to be similar to the awake state Barttfeld et al. In general, loss of consciousness under many anesthetics is thought to result from a disruption at the level of the thalamus Alkire ; Alkire and Miller ; Alkire et al.

Isoflurane hyperpolarizes thalamo-cortical neurons Langmoen et al. Isoflurane diminishes excitation by reducing glutamate release and increases inhibition via GABAergic mechanisms, thereby substantially altering neural activity in a dose dependent manner Joksovic and Todorovic ; Langmoen et al. This suggests that lower or intermediate levels of isoflurane-induced sedation may have different changes in functional connectivity compared to the deep levels of anesthesia used here.

The literature on the relationship between anesthesia and functional connectivity of thalamus is expansive and at times conflicting for comprehensive reviews see Hudetz ; Gozzi and Schwarz, Consistent with our current findings, many studies analyzing whole brain changes in functional connectivity between awake and anesthetized states find robust degradation of thalamocortical networks Akeju et al.

In support of these findings, other studies performed only in the anesthetized state found no functional connectivity with thalamus Vincent et al. In contrast, some studies did observe functional thalamocortical connectivity in the anesthetized state Schwarz et al. Differences in thalamocortical responsivity to anesthesia seem to reflect variations in anesthetic sensitivity for different thalamic nuclei, causing some thalamocortical connections under anesthesia to be lost and others to be maintained. As an example, primary somatosensory nuclei in the thalamus are known to continue to respond to sensory stimuli even under deep sedation, whereas higher order sensory thalamic nuclei lose their responses Diamond et al.

With regards to RS-fMRI functional connectivity, we have previously shown a more severe degradation of thalamocortical functional connectivity of cognitive circuits from a seed placed in infralimbic cortex between the awake and anesthetized states compared to primary somatosensory cortex thalamocortical connections Liang et al. Indeed, other studies looking purely at primary sensory networks do not report thalamocortical functional degradation at even high doses of anesthesia Liu et al.

These results seem to confirm that different thalamocortical circuits show varying sensitivity to anesthesia, particularly in terms of functional connectivity. In the analyses reported in this paper, we saw similar results. Wherein claustrum connectivity with mPFC and MD thalamus was degraded under anesthesia, bilateral connections with sensorimotor cortex persisted. This result may relate to the increased sensitivity of higher-order circuits to anesthetics, and may provide important clues to the emergence of the awake, conscious state out of these higher-order networks.

The reasons for these dramatic differences in thalamocortical functional connectivity patterns observed under different anesthetic regimes or across different thalamocortical circuits remains unresolved, but warrants caution when interpreting functional connectivity data. These disparities may be due to the particular anesthetic regimen employed, inter-species differences, dissimilarities in physiologic state of the subjects i.

Whether the claustrum circuit dynamics described here occur under different anesthetics and other species requires future studies. The mPFC is part of the rodent default mode network, which is thought to be active when the brain is idle, in the absence of other mental functions such as sensory perception and motor planning Fox et al.

By using a seed based analysis approach, our data suggest that the claustrum and MD thalamus are anatomically and functionally connected to mPFC, and thus may be involved in the rodent default mode network. Previous studies in both humans He et al. Our data expand on these studies to indicate that the claustrum is also functionally connected to the mPFC, and thus likely to influence the default mode network.

This finding provides indirect evidence for a role of the claustrum in supporting the awake state. Previous studies have suggested that the default mode network displays a decrease in functional connectivity during anesthesia induced loss of consciousness Vincent et al.

Thus, future studies investigating the relationship of the default mode network and loss of consciousness may reveal degradations in functional connectivity between mPFC and MD thalamus with the claustrum. Beyond the default mode network, the mPFC and MD circuits are believed to be involved in multiple cognitive processes reviewed in Mitchell Our data demonstrate that these brain regions have interhemispheric anatomical and functional connections with the claustrum.

Together, these findings suggest that the claustrum may play a role in mediating the interhemispheric coordination of cognitive related information. The data in our study shed light on the mechanisms underlying RS-fMRI and the limitations of its interpretability. A previous study using RS-fMRI in awake humans and primates suggests that functional networks resemble the underlying anatomical network structure, as determined by DTI Greicius et al. In contrast, another recent study emphasizes that the awake state demonstrates functional connections that exist beyond the constraints of the structural anatomical connectivity Barttfeld et al.

By comparing our RS-fMRI data to our anatomical tracing results, we showed that functional connectivity in the awake and anesthetized state can both differ from the underlying anatomical substrate. While the claustrum has strong anatomical connections with MD-thalamus, we found that this connection was most obviously detected by RS-fMRI only when the animal was awake. Furthermore, even though the anatomical data indicate that the claustrum is not monosynaptically connected with its counterpart in the opposite hemisphere, RS-fMRI revealed functional claustroclaustral connectivity in both the awake and anesthetized states, probably because of the strong interhemispheric anatomical connections between the claustrum and agranular motor cortex Smith and Alloway , ; Smith et al.

Hence, our results suggest a tenuous relationship between anatomical and functional connectivity, and this emphasizes the need for caution in interpreting RS-fMRI data, particularly when inferring structural connectivity from functional connectivity, even in the anesthetized state. A final complication of using isoflurane in our experiments is its vasoactive effects, which may alter the blood oxygen level dependent BOLD signal measured with fMRI.

Isoflurane is a potent vasodilator and it decreases brain temperature Masamoto and Kanno ; Shirey et al.

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These effects occur throughout the entire brain and therefore should affect all functional connections to the same extent, minimizing their impact on our results. Furthermore, though neurovascular coupling has been shown to be altered by isoflurane, the relationship between increases in neural activity and increases in BOLD persist, which suggests that the BOLD measurements in our study reflect underlying changes in neural activity Franceschini et al. All authors revised and approved the manuscript.

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