The Challenge of Understanding the Brain: Where We Stand in 2015

Lisman, John

doi:10.1016/j.neuron.2015.03.032

Cited by 79 publications

(39 citation statements)

References 259 publications

(274 reference statements)

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“…Deficits in working memory in patients with SCZ and/or 22q11DS are well documented 49, 50 . STP, an associative, short-lived synaptic strengthening, is considered a cellular correlate of short-term memory, a term often used synonymously with working memory 20, 51 . Consistent with this notion, deficits in STP are well established in animal models of SCZ and 22q11DS 12, 48, 52–54 .…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium

Devaraju

Eddins

et al. 2016

Mol Psychiatry

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Hemizygous deletion of a 1.5- to 3-megabase region on chromosome 22 causes 22q11.2 deletion syndrome (22q11DS), which constitutes one of the strongest genetic risks for schizophrenia. Mouse models of 22q11DS have abnormal short-term synaptic plasticity (STP) that contributes to working memory deficiencies similar to those in schizophrenia. We screened mutant mice carrying hemizygous deletions of 22q11DS genes and identified haploinsufficiency of Mrpl40 (mitochondrial large ribosomal subunit protein 40) as a contributor to abnormal STP. Two-photon imaging of the genetically encoded fluorescent calcium indicator GCaMP6, expressed in presynaptic cytosol or mitochondria, showed that Mrpl40 haploinsufficiency deregulates STP via impaired calcium extrusion from the mitochondrial matrix through the mitochondrial permeability transition pore. This led to abnormally high cytosolic calcium transients in presynaptic terminals and deficient working memory but did not affect long-term spatial memory. Thus, we propose that mitochondrial calcium deregulation is a novel pathogenic mechanism of cognitive deficiencies in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium

Devaraju

Eddins

et al. 2016

Mol Psychiatry

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“…Mental simulation offers a window into the mind, providing scientists with a powerful means to develop mechanistic models of memory by studying the top-down flow of information processing (Lisman, 2015). To date, the temporal dynamics of mental simulations are unknown, despite representing a unique component of memory and prospection that can provide insight into how features of memories are organized and used to anticipate future scenarios.…”

Section: Discussionmentioning

confidence: 99%

Mental simulation of routes during navigation involves adaptive temporal compression

2016

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Mental simulation is a hallmark feature of human cognition, allowing features from memories to be flexibly used during prospection. While past studies demonstrate the preservation of real-world features such as size and distance during mental simulation, their temporal dynamics remains unknown. Here, we compare mental simulations to navigation of routes in a large-scale spatial environment to test the hypothesis that such simulations are temporally compressed in an adaptive manner. Our results show that simulations occurred at 2.39x the speed it took to navigate a route, increasing in compression (3.57x) for slower movement speeds. Participant self-reports of vividness and spatial coherence of simulations also correlated strongly with simulation duration, providing an important link between subjective experiences of simulated events and how spatial representations are combined during prospection. These findings suggest that simulation of spatial events involve adaptive temporal mechanisms, mediated partly by the fidelity of memories used to generate the simulation.

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“…The power-of-two permutation-based computational logic can be executed in the cortex whether it has three or six layers (Barbas, 2015; Fournier et al, 2015), in the service of the fundamental cortical “processing unit” that has been long sought-after (Van Hemmen and Sejnowski, 2005; Rabinovich et al, 2008; Hill et al, 2012; Marcus et al, 2014; Adolphs, 2015; Lisman, 2015). In both the mouse RSC and hamster PrL, we showed that specific cells were concentrated in the superficial layers (L2/3), whereas general cells were enriched in the deep layers (L5/6).…”

Section: Discussionmentioning

confidence: 99%

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic

Xie

Fox

Liu

et al. 2016

Front. Syst. Neurosci.

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There is considerable scientific interest in understanding how cell assemblies—the long-presumed computational motif—are organized so that the brain can generate intelligent cognition and flexible behavior. The Theory of Connectivity proposes that the origin of intelligence is rooted in a power-of-two-based permutation logic (N = 2i–1), producing specific-to-general cell-assembly architecture capable of generating specific perceptions and memories, as well as generalized knowledge and flexible actions. We show that this power-of-two-based permutation logic is widely used in cortical and subcortical circuits across animal species and is conserved for the processing of a variety of cognitive modalities including appetitive, emotional and social information. However, modulatory neurons, such as dopaminergic (DA) neurons, use a simpler logic despite their distinct subtypes. Interestingly, this specific-to-general permutation logic remained largely intact although NMDA receptors—the synaptic switch for learning and memory—were deleted throughout adulthood, suggesting that the logic is developmentally pre-configured. Moreover, this computational logic is implemented in the cortex via combining a random-connectivity strategy in superficial layers 2/3 with nonrandom organizations in deep layers 5/6. This randomness of layers 2/3 cliques—which preferentially encode specific and low-combinatorial features and project inter-cortically—is ideal for maximizing cross-modality novel pattern-extraction, pattern-discrimination and pattern-categorization using sparse code, consequently explaining why it requires hippocampal offline-consolidation. In contrast, the nonrandomness in layers 5/6—which consists of few specific cliques but a higher portion of more general cliques projecting mostly to subcortical systems—is ideal for feedback-control of motivation, emotion, consciousness and behaviors. These observations suggest that the brain’s basic computational algorithm is indeed organized by the power-of-two-based permutation logic. This simple mathematical logic can account for brain computation across the entire evolutionary spectrum, ranging from the simplest neural networks to the most complex.

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The Challenge of Understanding the Brain: Where We Stand in 2015

Cited by 79 publications

References 259 publications

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium

Haploinsufficiency of the 22q11.2 microdeletion gene Mrpl40 disrupts short-term synaptic plasticity and working memory through dysregulation of mitochondrial calcium

Mental simulation of routes during navigation involves adaptive temporal compression

Brain Computation Is Organized via Power-of-Two-Based Permutation Logic

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