Research Advances in the Neuroinflammation in Alzheimer's Disease.

Alzheimer's disease(AD) is a chronic degenerative disease of the nervous system,and the pathological change of AD is the formation of senile plaques containing amyloid ß(Aß) and the neurofibrillary tangles. AD patients and animal models exhibit the over activation of microglia(MG) and astrocytes,causing neuroinflammation,leading to neuron death. Inhibition of MG activity can alleviate Aß plaques. A growing number of studies have found that neuroinflammation is involved in the development and progression of AD. This article reviews the role of neuroinflammation induced by MG,astrocytes,T lymphocyte,and monocyte-derived macrophages in the mechanism of AD.

Downregulation of cortical inhibition mediates ocular dominance plasticity during the critical period.

Monocular deprivation (MD) during the critical period (CP) shifts ocular dominance (OD) of cortical responsiveness toward the nondeprived eye. The synaptic mechanisms underlying MD-induced OD plasticity, in particular the contribution of cortical inhibition to the plasticity, have remained unsolved. In this study, using in vivo whole-cell voltage-clamp recordings, we revealed eye-specific excitatory and inhibitory synaptic inputs to layer 4 excitatory neurons in mouse primary visual cortex (V1) at a developmental stage close to the end of CP. We found in normally reared mice that ocular preference is primarily determined by the contralateral bias of excitatory input and that inhibition does not play an active role in shaping OD. MD results in a parallel reduction of excitation and inhibition driven by the deprived eye, while reducing the inhibition but preserving the excitation driven by the nondeprived eye. MD of longer periods causes larger changes in synaptic amplitude than MD of shorter periods. Furthermore, MD resulted in a shortening of onset latencies of synaptic inputs activated by both contralateral and ipsilateral eye stimulation, while the relative temporal relationship between excitation and inhibition driven by the same eye was not significantly affected. Our results suggest that OD plasticity is largely attributed to a reduction of feedforward input representing the deprived eye, and that an unexpected weakening of cortical inhibitory connections accounts for the increased responsiveness to the nondeprived eye.

Broadening of cortical inhibition mediates developmental sharpening of orientation selectivity.

Orientation selectivity (OS) of visual cortical neurons is progressively sharpened during development. However, synaptic circuit mechanisms underlying the OS sharpening remain unclear. In the current study, in vivo whole-cell voltage-clamp recordings from layer 4 excitatory neurons in the developing mouse primary visual cortex revealed changes of orientation tuning profiles of their excitatory and inhibitory inputs during a post-eye-opening period when OS of their spiking responses becomes sharpened. In addition to a parallel strengthening of excitation and inhibition during this developmental period, the orientation tuning of excitatory inputs keeps relatively constant, whereas the tuning of inhibitory inputs is broadened, and becomes significantly broader than that of excitatory inputs. Neuron modeling and dynamic-clamp recording demonstrated that this developmental broadening of the inhibitory tuning is sufficient for sharpening OS. Depriving visual experience by dark rearing impedes the normal developmental strengthening of excitation, but a similar broadening of inhibitory tuning, likely caused by a nonselective strengthening of inhibitory connections, results in the apparently normal OS sharpening in excitatory neurons. Our results thus provide the first demonstration that an inhibitory synaptic mechanism can primarily mediate the functional refinement of cortical neurons.

Broadening of inhibitory tuning underlies contrast-dependent sharpening of orientation selectivity in mouse visual cortex.

Orientation selectivity (OS) in the visual cortex has been found to be invariant to increases in stimulus contrast, a finding that cannot be accounted for by the original, purely excitatory Hubel and Wiesel model. This property of OS may be important for preserving the quality of perceived stimulus across a range of stimulus intensity. The synaptic mechanisms that can prevent a broadening of OS caused by contrast-dependent strengthening of excitatory inputs to cortical neurons remain unknown. Using in vivo loose-patch recordings, we found in excitatory neurons in layer 4 of mouse primary visual cortex (V1) that the spike response to the preferred orientation was elevated as contrast increased while that to the orthogonal orientation remained unchanged, resulting in an overall sharpening rather than a weakening of OS. Whole-cell voltage-clamp recordings further revealed that contrast increases resulted in a scaling up of excitatory conductance at all stimulus orientations. Inhibitory conductance was enhanced at a similar level as excitation for the preferred orientation, but at a significantly higher level for the orthogonal orientation. Modeling revealed that the resulting broadening of inhibitory tuning is critical for maintaining and sharpening OS at high contrast. Finally, two-photon imaging guided recordings from parvalbumin-positive (PV) inhibitory neurons revealed that the broadening of inhibition can be attributed to a contrast-dependent broadening of spike-response tuning of PV neurons. Together our results suggest that modulation of synaptic inhibition in the mouse V1 cortical circuit preserves the sharpness of response selectivity during changes of stimulus strength.

Visual representations by cortical somatostatin inhibitory neurons--selective but with weak and delayed responses.

Somatostatin-expressing inhibitory (SOM) neurons in the sensory cortex consist mostly of Martinotti cells, which project ascending axons to layer 1. Due to their sparse distribution, the representational properties of these neurons remain largely unknown. By two-photon imaging guided cell-attached recordings, we characterized visual response and receptive field (RF) properties of SOM neurons and parvalbumin-expressing inhibitory (PV) neurons genetically labeled in the mouse primary visual cortex. In contrast to PV neurons, SOM neurons exhibit broader spikes, lower spontaneous firing rates, smaller On/Off subfields, and broader ranges of basic RF properties such as On/Off segregation, orientation and direction tunings. Notably, the level of orientation and direction selectivity is comparable to that of excitatory neurons, from weakly-tuned to highly selective, whereas PV neurons are in general unselective. Strikingly, the evoked spiking responses of SOM cells are ∼3- to 5-fold weaker and 20-25 ms delayed compared with those of PV neurons. The onset latency of the latter is consistent with that of inhibitory input to excitatory neurons. These functional differences between SOM and PV neurons exist in both layer 2/3 and 4. Our results suggest that SOM and PV neurons engage in cortical circuits in different manners: while PV neurons provide fast, strong but untuned feedforward inhibition to excitatory neurons, likely serving as a general gain control for the processing of ascending inputs, SOM neurons with their selective but delayed and weak inhibition may provide more specific gating of later arriving intracortical excitatory inputs on the distal dendrites.

Exposure to chronic constant light impairs spatial memory and influences long-term depression in rats.

Exposure to chronic constant light (CCL) influences circadian rhythms and evokes stress. Since hippocampus is sensitive to stress, which facilitates long-term depression (LTD) in the hippocampal CA1 area, we examined whether CCL exposure influenced hippocampus-dependent spatial memory and synaptic plasticity in Wistar rats. Here we report that CCL exposure (3 weeks) disrupted 24-h cycle of locomotion activity in open field test. These rats showed shorter escape latency during initial phase of spatial learning but impaired hippocampus-dependent spatial memory without affecting the visual platform learning task in Morris water maze (MWM) compared with control rats. This effect may be due to stress adaptation as reflected by reduced thigmotaxis and anxiety-like behaviors in CCL rats. Moreover, in CA1 area of the hippocampal slices, CCL rats failed to show LTD by low frequency stimulation (LFS, 900 pulses, 1 Hz), while showed decreased short-term depression compared with control rats indicating the induction of LTD was influenced by CCL exposure. Furthermore, additional acute stress enabled LFS to induce LTD in control rats but not in CCL rats. Thus, these results suggested that CCL exposure impaired spatial memory and influenced hippocampal LTD, which may be due to stress adaptation.

Chronic constant light-induced hippocampal late-phase long-term potentiation impairment in vitro is attenuated by antagonist of D1/D5 receptors.

Previous study reported that chronic constant light exposure caused hippocampus-dependent long-term memory deficit. However, the underlying cellular mechanism of this impairment is still unclear. Multiple lines of evidence indicated that long-term potentiation (LTP) is a cellular model for memory formation. Here we found that, by recording of field excitatory postsynaptic potential (fEPSP) in vitro, chronic constant light (CCL, 3 weeks) exposure impaired the late long-term potentiation (L-LTP), but not early long-term potentiation (E-LTP) and basal transmission in Schaffer collateral (SC)-CA1 synapses of hippocampal slices from rats. Because L-LTP depends on D1/D5 receptors, we examined whether interference of D1/D5 receptors can modulate L-LTP of CCL rats. Bath application of D1/D5 receptors antagonist SCH23390 (1µM) blocked L-LTP in control rats and attenuated the impaired L-LTP in CCL rats. In contrast, pre-incubation of D1/D5 receptors agonist SKF38393 (25µM) occluded further L-LTP in control rats while exacerbated the L-LTP impairment in CCL rats. These results suggested that CCL-induced L-LTP impairment can be modulated by D1/D5 receptors. Our findings may contribute to the further understanding of synaptic plasticity mechanism underlying hippocampal long-term memory impairment induced by circadian rhythm disruption.

Functional response properties of VIP-expressing inhibitory neurons in mouse visual and auditory cortex.

Despite accounting for about 20% of all the layer 2/3 inhibitory interneurons, the vasoactive intestinal polypeptide (VIP) expressing neurons remain the least thoroughly studied of the major inhibitory subtypes. In recent studies, VIP neurons have been shown to be activated by a variety of cortico-cortical and neuromodulatory inputs, but their basic sensory response properties remain poorly characterized. We set out to explore the functional properties of layer 2/3 VIP neurons in the primary visual (V1) and primary auditory cortex (A1), using two-photon imaging guided patch recordings. We found that in the V1, VIP neurons were generally broadly tuned, with their sensory response properties resembling those of parvalbumin (PV) expressing neurons. With the exception of response latency, they did not exhibit a significant difference from PV neurons across any of the properties tested, including overlap index, response modulation, orientation selectivity, and direction selectivity. In the A1, on the other hand, VIP neurons had a strong tendency to be intensity selective, which is a property associated with a subset of putative pyramidal cells and virtually absent in PV neurons. VIP neurons had a best intensity that was significantly lower than that of PV and putative pyramidal neurons. Finally, sensory evoked spike responses of VIP neurons were delayed relative to pyramidal and PV neurons in both the V1 and A1. Combined, these results demonstrate that the sensory response properties of VIP neurons do not fit a simple model of being either PV-like broadly tuned or pyramidal-like narrowly tuned. Instead, the selectivity pattern varies with sensory area and can even be, as in the case of low sound intensity responsiveness, distinct from both PV and pyramidal neurons.

Ocular dominance plasticity disrupts binocular inhibition-excitation matching in visual cortex.

BACKGROUND: To ensure that neuronal networks function in a stable fashion, neurons receive balanced inhibitory and excitatory inputs. In various brain regions, this balance has been found to change temporarily during plasticity. Whether changes in inhibition have an instructive or permissive role in plasticity remains unclear. Several studies have addressed this question using ocular dominance plasticity in the visual cortex as a model, but so far, it remains controversial whether changes in inhibition drive this form of plasticity by directly affecting eye-specific responses or through increasing the plasticity potential of excitatory connections. RESULTS: We tested how three major classes of interneurons affect eye-specific responses in normally reared or monocularly deprived mice by optogenetically suppressing their activity. We find that in contrast to somatostatin-expressing or vasoactive intestinal polypeptide-expressing interneurons, parvalbumin (PV)-expressing interneurons strongly inhibit visual responses. In individual neurons of normal mice, inhibition and excitation driven by either eye are balanced, and suppressing PV interneurons does not alter ocular preference. Monocular deprivation disrupts the binocular balance of inhibition and excitation in individual neurons, causing suppression of PV interneurons to change their ocular preference. Importantly, however, these changes do not consistently favor responses to one of the eyes at the population level. CONCLUSIONS: Monocular deprivation disrupts the binocular balance of inhibition and excitation of individual cells. This disbalance does not affect the overall expression of ocular dominance. Our data therefore support a permissive rather than an instructive role of inhibition in ocular dominance plasticity.

Broad inhibition sharpens orientation selectivity by expanding input dynamic range in mouse simple cells.

Orientation selectivity (OS) is an emergent property in the primary visual cortex (V1). How OS arises from synaptic circuits remains unsolved. Here, in vivo whole-cell recordings in the mouse V1 revealed that simple cells received broadly tuned excitation and even more broadly tuned inhibition. Excitation and inhibition shared a similar orientation preference and temporally overlapped substantially. Neuron modeling and dynamic-clamp recording further revealed that excitatory inputs alone would result in membrane potential responses with significantly attenuated selectivity, due to a saturating input-output function of the membrane filtering. Inhibition ameliorated the attenuation of excitatory selectivity by expanding the input dynamic range and caused additional sharpening of output responses beyond unselectively suppressing responses at all orientations. This "blur-sharpening" effect allows selectivity conveyed by excitatory inputs to be better expressed, which may be a general mechanism underlying the generation of feature-selective responses in the face of strong excitatory inputs that are weakly biased.