The Structure, Dynamics and Function of Neural Micro-Circuits for Perception and Behavior

Editors

Yoshiyuki Kubota

National Institute for Physiological Sciences (NIPS)

Allan T Gulledge

Dartmouth College

M. Victoria Puig

Catalan Institute of Nanoscience and Nanotechnology (CIN2)

Impact

Anatomical connectivity between pairs of mitral cells via one granule cell. (A) Top: Top view of the dendritic fields of MC A (magenta), a second MC B (gray) at distance dAB, and a GC (green) within the overlap area F of the MCs’ dendritic fields. Middle: Illustration of symmetry in NA(r) and NB(r). Bottom: Geometrical parameters relevant for the calculus in Eqs 9, 10 (see also Table 2). rA, rB: distance of GC from MC A resp. B. α: angle between the position of GC soma rA and dAB. αMAX: maximally possible α for the respective dAB. x: distance of projection of GC position onto dAB from MC A; relevant for integration. The gray rectangles represent the integration increments dF. (B) Probability PAB of a GC at position rA to connect to both A and B (Eq. 6), plotted for a set of distances dAB between mitral cells A and B (0–1400 μm). The righthand peak in the curves for 200–700 μm is due to the increased synaptic density around the soma of MC B. Parameters as given in Table 1. (C) IAB: correction of PAB for a distance-dependent reduction in IPSP impact because of attenuation (Figure 2C, Eq. 7).

Original Research

22 July 2022

Anatomical and Functional Connectivity at the Dendrodendritic Reciprocal Mitral Cell–Granule Cell Synapse: Impact on Recurrent and Lateral Inhibition

S. Sara Aghvami

, 1 more and

Veronica Egger

4,386 views

8 citations

Agar dispenser. (A) Configuration of the agar dispenser system. A microcontroller connected to the PC1 regulates the stepping and servo motors, forming two linear actuators. The orthogonal linear actuators push agar in the agar mold twice (Push 1 and 2), which creates an agar cube. We used another PC (PC2) to observe and record mouse behavior with two cameras. Push timings and camera triggers are stored on the PC1 by a data acquisition board. (B) Photograph showing the top view of the behavior task system. (C) Schematic of the agar mold. Successive pushes by orthogonal plungers (Push 1 → Push 2) create and present the agar cube in front of a mouse. (D) A schematic diagram of the molds before and after extrusion of all the agars is shown. Approximately 20 agar cubes are produced from the start to the end of this process. The position of optical sensors determined the start and end positions of the agar extrusion. The main parts are indicated by the following colors; stepping motor: red, linear guide: green, ball screw: dark gray, push 1 plunger: orange, and connecter between linear guide, ball screw, and push 1 plunger: blue. (E) Schematic of the push 2. For each agar cube (one trial), the agar extruded by push 1 plunger converted into a cube by push 2. The main parts are color-coded as follows; stepping motor: red, linkage: dark gray, linear guide: green, and push 2 plunger: orange. (F) Photograph of a side view of the agar mold and the push 2 mechanism. (G) Apparatus for fixing the head of mice. A manual XY stage (blue square) and a laboratory jack (red square) were placed at the bottom of the device that fixes the mouse head (green square) so that the position of the mouse can be adjusted. (H) Photograph of the whole system (the agar dispenser system with the head fix apparatus).

Methods

12 May 2022

A Novel Device of Reaching, Grasping, and Retrieving Task for Head-Fixed Mice

Satoshi Manita

, 1 more and

Kazuo Kitamura

4,848 views

1 citations

Axonal projections from the LPN and LGN in V1. (A) An anterograde labeling of the LGN and LPN axons with different fluorescent proteins. (B) A local injection of AAV-GFP in the LGN (upper) and AAV-tdTomato in the LPN (lower). (C) The distribution of the LGN (left) and LPN (middle) axons in V1 of the coronal slice. LGN axons project mainly to the layer 4, while LPN axons project mainly to the layer 1 (right). LPN, lateral posterior nucleus; LGN, lateral geniculate nucleus; V1, primary visual cortex; AAV-GFP, adeno-associated virus-green fluorescent protein.

Original Research

28 February 2022

Response Selectivity of the Lateral Posterior Nucleus Axons Projecting to the Mouse Primary Visual Cortex

Satoru Kondo

, 1 more and

Kenichi Ohki

7,482 views

2 citations

Original Research

18 February 2022

Cell-Type Specific Neuromodulation of Excitatory and Inhibitory Neurons via Muscarinic Acetylcholine Receptors in Layer 4 of Rat Barrel Cortex

Guanxiao Qi

and

Dirk Feldmeyer

7,367 views

9 citations

Sensitivity of network dynamic to hub attack is mostly attributed to attacks on L5 PCs. (A) Percentages of synapses for excitatory (brown-red arrows) and inhibitory (blue-green arrows) connections in the NMC microcircuit (layer 1 omitted). Arrow width and corresponding numbers indicate the percentage of total synapses formed by this pathway (omitted for pathways with <1% of synapses). The total percentage of plotted synapses is 98%; the remaining 2% originate in layer 1. Rectangle sizes are proportional to the sizes of the corresponding number of excitatory or inhibitory populations. (B) The connectivity among layers and cell-types is visualized using the force-directed graph algorithm (see section “Materials and Methods”). The network is composed of 55 morphological cell-types (circular nodes, colors match to that in A); edges strength corresponds to pairwise connection probabilities. Strongly connected cell-types are displayed closer in space. (C) Same as (B), but for the network following an attack on 15,000 hub neurons. Note the disappearance of the large nodes in Layer 5. (D–G) Different quantification of network activity for layer-specific hub attack, global hub attack and random nodes attack. (D) Number of bursts/sec, (E) average network firing rate, (F) coefficient of variation, (G) global SPIKE synchronization measure (see section “Materials and Methods”). Note that attack of L5 pyramidal cells is the most disruptive layer attack.

Original Research

24 September 2021

The Role of Hub Neurons in Modulating Cortical Dynamics

Eyal Gal

, 5 more and

Idan Segev

8,604 views

16 citations

Proposed mechanisms for establishing stereotyped patterns of synaptic connectivity in the neocortex. (A) Predictable patterns of synaptic connectivity may be defined by anatomical relationships between presynaptic axons and postsynaptic dendrites. For example, the axodendritic overlap between Input 1 (green) and the two pyramidal cell types (magenta, blue) precludes synapse formation with the blue cell type. The axodendritic overlap of Input 2 (orange) and the two pyramidal cell types predicts a higher probability of connection with the blue type than the magenta type. (B) Fine-scale neurite geometry such as axon tortuosity and dendritic spine outgrowth may contribute to synaptic partner selection. Growth patterns of axons and dendrites at small scales alter the amount of apposed membrane between cells, and thus the number of potential synaptic sites. Inhibitory interneuron axons (Inh, blue) in the cortex are highly tortuous, which can increase potential sites of contact with the dendrites of preferred synaptic partners, allowing the formation of more synapses between them. The axons of excitatory pyramidal neurons (Exc, orange) are more linear but directed dendritic spine growth in postsynaptic neurons (Exc, magenta) could also allow for the preferential formation of synaptic sites. (C) Lineage relationships affect synaptic connectivity. Clonally related pyramidal cells (sister cells) arising from the same neural progenitor lineage are preferentially interconnected by gap junctions () during the first postnatal week (postnatal day 0–6; P0–P6). These gap junctions disappear during the second postnatal week (∼P10+), and chemical synapses are preferentially formed between clonally related pyramidal cells. (D) Activity-dependent plasticity may guide cell-type biased synaptic targeting. Different axonal inputs to a cortical cell type may have distinct neural activity patterns, and synapses between specific cell-type combinations may be selectively strengthened (orange input) or weakened (green input) through activity-dependent mechanisms, leading to preferential connectivity between cortical cell types. (E) Specific expression of recognition molecules may mediate cell-type or domain-specific synaptic targeting and synapse-type-specific functional properties. During development, preferred synaptic partner cell types may express cognate receptors and ligands (red) on the pre- (orange) and postsynaptic processes (purple). These molecular signals guide growth and synaptogenesis, leading to cell-type-biased connectivity and function in adulthood.

Review

24 September 2021

Mechanisms Underlying Target Selectivity for Cell Types and Subcellular Domains in Developing Neocortical Circuits

Alan Y. Gutman-Wei

and

Solange P. Brown

8,266 views

7 citations

Review

12 July 2021

Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors

Sha-Sha Yang

, 2 more and

Wen-Jun Gao

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

13,198 views

35 citations

Summary diagram: long-range VIP-expressing neuron projections. Top right: schematic representation of auditory cortex injection with AAV-flex-ChRimson-tdTomato. VIP long-range axons were found in several areas: AC, auditory cortex, right, and left; cc, corpus callosum; ipsilateral ICe, inferior colliculus, external; ipsilateral IC, inferior colliculus; ipsilateral LA, lateral amygdala; ipsilateral MGB, medial geniculate body, ipsilateral SC, superior colliculus; ipsilateral STR, striatum; ipsilateral TeA, temporal association cortex.

Original Research

23 July 2021

Corticofugal VIP Gabaergic Projection Neurons in the Mouse Auditory and Motor Cortex

Alice Bertero

, 1 more and

Alfonso junior Apicella

6,021 views

9 citations

Distribution patterns of bilateral inputs in PAL subregions between the two CA1 tracing groups. (A) Representative images showing MS and NDB inputs to the dorsal or ventral CA1 PNs. Scale bar: 500 μm. (B) CSI of the inputs in bilateral PAL subregions. (C) Distribution patterns of the input neurons along the RC axis in the bilateral MS or NDB. (D) The contralateral-ipsilateral distribution patterns of monosynaptic inputs in MS or NDB of two tracing groups. (E) The dorsal-ventral distribution patterns of monosynaptic inputs in MS or NDB of two tracing groups. n.s., no significant difference; **P < 0.01.

Original Research

14 April 2021

Whole-Brain Mapping the Direct Inputs of Dorsal and Ventral CA1 Projection Neurons

Sijue Tao

, 7 more and

Fuqiang Xu

17,322 views

43 citations

$The NLGN3-R451C mutation causes the enhancement of inhibitory synaptic transmission and the elevation of inhibition/excitation ratio of synaptic inputs to PCs. (A) Representative traces of mIPSC recorded from PCs of wild-type (upper trace) and NLGN3-R451C mutant (lower trace) mice (top) at Vh of −70 mV in the presence of 1 μM tetrodotoxin, 10 μM NBQX, and 5 μM R-CPP (N = 3/group). Scale bars, 250 ms and 50 pA. Cumulative distribution plots and summary bar graphs for the mIPSC amplitude (lower left; inset shows the average mIPSC amplitude) and for the inter-event interval (lower right; inset shows the average mIPSC frequency) in PCs of wild-type and NLGN3-R451C mutant mice aged P21–P35. For the mIPSC amplitude, ***p < 0.0001 by Kolmogorov-Smirnov test in the cumulative distribution plot and ***p = 0.0002 by Mann-Whitney U test in the bar graph. For the inter-event interval, p = 0.99 by Kolmogorov-Smirnov test in the cumulative distribution plot and p = 0.9 by Mann-Whitney U test in the bar graph. (B) Summary graph for the mIPSC amplitude of wild-type (open columns) and NLGN3-R451C mutant (orange columns) mice at indicated ages. Note that the mean amplitudes of mIPSCs in NLGN3-R451C mutant mice are significantly larger than those of wild-type mice during postnatal development (P7–P9, *p = 0.029; P10–P12, **p = 0.0053; P13–P15, **p = 0.0083; P16–P20, *p = 0.024 by Mann-Whitney U test). (C) Representative traces of mEPSC recorded from PCs of wild-type (upper trace) and NLGN3-R451C mutant (lower trace) mice (top) at Vh of −70 mV in the presence of 1 μM tetrodotoxin and 100 μM PTX (N = 3/group). Scale bars, 250 ms and 20 pA. Cumulative distribution plots for the mEPSC amplitude (lower left; inset shows the average mEPSC amplitude) and for the inter-event interval (lower right; inset shows the average mEPSC frequency) in PCs of wild-type and NLGN3-R451C mutant mice aged P21–P35. For the mEPSC amplitude, p = 0.17 by Kolmogorov-Smirnov test in the cumulative distribution plot and p = 0.40 by Mann-Whitney U test in the bar graph. For the inter-event interval, p = 0.84 by Kolmogorov-Smirnov test in the cumulative distribution plot and p = 0.59 by Mann-Whitney U test in the bar graph. (D) Summary graph for the mEPSC amplitude of wild-type (open columns) and NLGN3-R451C mutant (orange columns) mice at indicated ages (P6–P9, p = 0.074; P10–P12, p = 0.76; P13–P15, p = 0.350; P16–P20, p = 0.10 by Mann-Whitney U test). (E) Representative traces of mIPSC recorded from PCs of wild-type (upper) and NLGN3-R451C mutant (lower) mice at P10 in the presence of 1 μM tetrodotoxin, 10 μM NBQX, and 5 μM R-CPP. Vh = −70 mV. Scale bars, 250 ms and 100 pA. (F) Cumulative fractions of the rise time of small (<100 pA) (gray dotted line) and large (>100 pA) (black line) mIPSCs in wild-type (left) and NLGN3-R451C mutant (right) mice from P10 to P12. ***p < 0.0001 by Kolmogorov-Smirnov test for both genotypes. (G) Summary bar graphs for the mIPSC amplitude for all, small and large events in wild-type (open columns) and NLGN3-R451C mutant (orange columns) mice from P10 to P12. **p = 0.0053 (All); **p = 0.0014 (Small); *p = 0.0484 (Large) by Mann-Whitney U test. (H) Experimental protocol used to measure the inhibition/excitation ratio. (I) Representative traces of evoked AMPAR- and GABAAR-mediated synaptic currents in wild-type (left) and NLGN3-R451C mutant (right) mice. Scale bars, 10 ms and 200 pA. (J) Amplitudes of AMPAR- (left) and GABAAR- (right) mediated synaptic currents from wild-type (black) and NLGN3-R451C mutant (orange) mice. (K) Average inhibition/excitation ratio from wild-type (open column) and NLGN3-R451C mutant (orange column) mice aged P19–P25. ***p = 0.0004 by Mann-Whitney U test. Data are expressed as mean ± SD. Total number of cells recorded/total number of mice used is indicated within or beneath individual columns.$

Original Research

28 June 2021

An Autism-Associated Neuroligin-3 Mutation Affects Developmental Synapse Elimination in the Cerebellum

Esther Suk King Lai

, 6 more and

Masanobu Kano

9,226 views

27 citations

Original Research

26 November 2020

Learning-Dependent Dendritic Spine Plasticity Is Reduced in the Aged Mouse Cortex

Lianyan Huang

, 3 more and

Guang Yang

Aging increases dendritic spine elimination in the sensory cortex. (A) In vivo time-lapse imaging of the same dendritic segments over 2 and 14 days in the sensory cortex of young and old mice. Filled and empty arrowheads indicate dendritic spines that were formed and eliminated relative to the first view, respectively. Asterisks indicate filopodia. Scale bar, 2 μm. (B) Percentages of dendritic spines that were formed and eliminated over 2 days. (C) Percentages of dendritic spines that were formed and eliminated over 14 days. (D) The density of dendritic spines on the apical tuft dendrites of L5 pyramidal neurons in young adult and old mice. Throughout, individual circles represent data from a single mouse. Summary data are presented as mean ± SEM. *P < 0.05 by two-tailed Mann–Whitney test.

Aging is accompanied by a progressive decrease in learning and memory function. Synaptic loss, one of the hallmarks of normal aging, likely plays an important role in age-related cognitive decline. But little is known about the impact of advanced age on synaptic plasticity and neuronal function in vivo. In this study, we examined the structural dynamics of postsynaptic dendritic spines as well as calcium activity of layer 5 pyramidal neurons in the cerebral cortex of young and old mice. Using transcranial two-photon microscopy, we found that in both sensory and motor cortices, the elimination rates of dendritic spines were comparable between young (3–5 months) and mature adults (8–10 months), but seemed higher in old mice (>20 months), contributing to a reduction of total spine number in the old brain. During the process of motor learning, old mice compared to young mice had fewer new spines formed in the primary motor cortex. Motor training-evoked somatic calcium activity in layer 5 pyramidal neurons of the motor cortex was also lower in old than young mice, which was associated with the decline of motor learning ability during aging. Together, these results demonstrate the effects of aging on learning-dependent synapse remodeling and neuronal activity in the living cortex and suggest that synaptic deficits may contribute to age-related learning impairment.

5,976 views

22 citations