Multisensory integration in the mammalian brain: diversity and flexibility in health and disease.

Multisensory integration (MSI) occurs in a variety of brain areas, spanning cortical and subcortical regions. In traditional studies on sensory processing, the sensory cortices have been considered for processing sensory information in a modality-specific manner. The sensory cortices, however, send the information to other cortical and subcortical areas, including the higher association cortices and the other sensory cortices, where the multiple modality inputs converge and integrate to generate a meaningful percept. This integration process is neither simple nor fixed because these brain areas interact with each other via complicated circuits, which can be modulated by numerous internal and external conditions. As a result, dynamic MSI makes multisensory decisions flexible and adaptive in behaving animals. Impairments in MSI occur in many psychiatric disorders, which may result in an altered perception of the multisensory stimuli and an abnormal reaction to them. This review discusses the diversity and flexibility of MSI in mammals, including humans, primates and rodents, as well as the brain areas involved. It further explains how such flexibility influences perceptual experiences in behaving animals in both health and disease. This article is part of the theme issue 'Decision and control processes in multisensory perception'.

Reduced activity of parvalbumin-positive interneurons in the posterior parietal cortex causes visually dominant multisensory decisions in freely navigating mice.

Multisensory integration is vital for animals to make optimal decisions in a complicated sensory environment. However, the neural mechanisms for flexible multisensory behaviors are not well understood. Here, we found that mice exhibit auditory-dominant decisions in the head-fixed and stationary state and switch to make visual-dominant decisions in the freely navigating state to resolve audiovisual conflicts. To understand the neural mechanism of the state-dependent switch in multisensory decisions, we performed in vivo calcium imaging of parvalbumin-expressing (PV+) inhibitory neurons in the posterior parietal cortex (PPC), which are known to mediate auditory dominance in the resolution of audiovisual conflicts, in mice on the treadmill. In the stationary state, the PPC PV+ neurons showed similar amounts of evoked activity in responses to auditory and visual stimuli and enhanced responses to the multisensory audiovisual stimuli. Conversely, when mice were running on a treadmill, the PV+ neurons lost auditory responses and did not show any multisensory enhancement in their activity. When we optogenetically activated the PPC PV+ neurons in mice freely navigating the T-maze, the mice made more auditory-dominant decisions without changes in unisensory decisions. Our data demonstrate that the PPC PV+ neurons lost their ability to integrate auditory information with the visual one during active navigation. This modulation of the PPC PV+ neuron activity is critical for animals to make adaptive multisensory decisions according to their behavioral states.

Gated feedforward inhibition in the frontal cortex releases goal-directed action.

Cortical circuits process both sensory and motor information in animals performing perceptual tasks. However, it is still unclear how sensory inputs are transformed into motor signals in the cortex to initiate goal-directed actions. In this study, we found that a visual-to-motor inhibitory circuit in the anterior cingulate cortex (ACC) triggers precise action in mice performing visual Go/No-go tasks. Three distinct features of ACC neurons-visual amplitudes of sensory neurons, suppression times of motor neurons and network activity from other neurons-predicted response times of the mice. Moreover, optogenetic activation of visual inputs in the ACC, which drives fast-spiking sensory neurons, prompted task-relevant actions in mice by suppressing ACC motor neurons and disinhibiting downstream striatal neurons. Notably, when mice terminated actions in response to stop signals, both motor neuron and network activity increased. Collectively, our data demonstrate that visual inputs to the frontal cortex trigger gated feedforward inhibition to initiate goal-directed actions.

NGL-1/LRRC4C-Mutant Mice Display Hyperactivity and Anxiolytic-Like Behavior Associated With Widespread Suppression of Neuronal Activity.

Netrin-G ligand-1 (NGL-1), encoded by Lrrc4c, is a post-synaptic adhesion molecule implicated in various brain disorders, including bipolar disorder, autism spectrum disorder, and developmental delay. Although previous studies have explored the roles of NGL-1 in the regulation of synapse development and function, the importance of NGL-1 for specific behaviors and the nature of related neural circuits in mice remain unclear. Here, we report that mice lacking NGL-1 (Lrrc4c-/- ) show strong hyperactivity and anxiolytic-like behavior. They also display impaired spatial and working memory, but normal object-recognition memory and social interaction. c-Fos staining under baseline and anxiety-inducing conditions revealed suppressed baseline neuronal activity as well as limited neuronal activation in widespread brain regions, including the anterior cingulate cortex (ACC), motor cortex, endopiriform nucleus, bed nuclei of the stria terminalis, and dentate gyrus. Neurons in the ACC, motor cortex, and dentate gyrus exhibit distinct alterations in excitatory synaptic transmission and intrinsic neuronal excitability. These results suggest that NGL-1 is important for normal locomotor activity, anxiety-like behavior, and learning and memory, as well as synapse properties and excitability of neurons in widespread brain regions under baseline and anxiety-inducing conditions.

Bortezomib-based strategy with autologous stem cell transplantation for newly diagnosed multiple myeloma: a phase II study by the Japan Study Group for Cell Therapy and Transplantation (JSCT-MM12).

BACKGROUND: The Japan Study Group for Cell Therapy and Transplantation (JSCT) organized a phase II study to evaluate the efficacy and safety of a treatment protocol (JSCT-MM12) for multiple myeloma (MM) patients who were previously untreated and transplantation-eligible. Since bortezomib-based therapy is known to be effective for MM, the protocol is intensified more than the previous protocol (JSCT-MM10) and comprised the subsequent treatments: bortezomib + cyclophosphamide + dexamethasone (VCD) induction; bortezomib + high-dose-melphalan (B-HDM) conditioning with autologous stem cell transplantation (ASCT); bortezomib + thalidomide + dexamethasone (VTD) consolidation; and lenalidomide (LEN) maintenance. METHODS: Sixty-four symptomatic patients aged between 20 and 65 years were enrolled for treatment and received three cycles of VCD, followed by cyclophosphamide administration for autologous stem cell harvest and B-HDM/ASCT, and subsequently two cycles of VTD, after that LEN for 1 year. RESULTS: Complete response (CR)/stringent CR (sCR) rates for induction, ASCT, consolidation, and maintenance therapies were 20, 39, 52, and 56%, respectively. The grade 3/4 toxicities (≥ 10%) with VCD treatment included neutropenia (27%), anemia (19%), and thrombocytopenia (11%). There was no treatment-related mortality. After median follow-up of 41 months, estimated 3-year progression-free survival (PFS) and overall survival (OS) rates were 64% and 88%, respectively. The high-risk group revealed lower CR/sCR, PFS, and OS than the standard-risk group. CONCLUSIONS: The study revealed that the treatment protocol consisting of VCD induction, B-HDM/ASCT followed by VTD consolidation, and LEN maintenance could produce highly beneficial responses and favorable tolerability in newly diagnosed MM. However, future study is required for improving treatment in the high-risk group.

Bottom-up and top-down modulation of multisensory integration.

Sensory perception in the real world requires proper integration of different modality inputs. Process of multisensory integration is not uniform. It varies from individual to individual and changes at different behavioral states of the animal. What factors affect multisensory integration? How does the mammalian brain reconstruct a multisensory world at different states? Here, we summarize recent findings on bottom-up and top-down factors that can modulate sensory processing and multisensory integration. We discuss cortical circuits that are responsible for modulation of multisensory processing based on recent rodent studies. We suggest that multisensory information is not a simple, fixed signal in the brain. Multisensory processing is dynamically modulated in the mammalian brain and leads to a unique and subjective experience of perception.

A Neural Circuit for Auditory Dominance over Visual Perception.

When conflicts occur during integration of visual and auditory information, one modality often dominates the other, but the underlying neural circuit mechanism remains unclear. Using auditory-visual discrimination tasks for head-fixed mice, we found that audition dominates vision in a process mediated by interaction between inputs from the primary visual (VC) and auditory (AC) cortices in the posterior parietal cortex (PTLp). Co-activation of the VC and AC suppresses VC-induced PTLp responses, leaving AC-induced responses. Furthermore, parvalbumin-positive (PV+) interneurons in the PTLp mainly receive AC inputs, and muscimol inactivation of the PTLp or optogenetic inhibition of its PV+ neurons abolishes auditory dominance in the resolution of cross-modal sensory conflicts without affecting either sensory perception. Conversely, optogenetic activation of PV+ neurons in the PTLp enhances the auditory dominance. Thus, our results demonstrate that AC input-specific feedforward inhibition of VC inputs in the PTLp is responsible for the auditory dominance during cross-modal integration.

Selectivity of Neuromodulatory Projections from the Basal Forebrain and Locus Ceruleus to Primary Sensory Cortices.

UNLABELLED: Acetylcholine and noradrenaline are major neuromodulators that affect sensory processing in the cortex. Modality-specific sensory information is processed in defined areas of the cortex, but it is unclear whether cholinergic neurons in the basal forebrain (BF) and noradrenergic neurons in the locus ceruleus (LC) project to and modulate these areas in a sensory modality-selective manner. Here, we mapped BF and LC projections to different sensory cortices of the mouse using dual retrograde tracing. We found that while the innervation of cholinergic neurons into sensory cortices is predominantly modality specific, the projections of noradrenergic neurons diverge onto multiple sensory cortices. Consistent with this anatomy, optogenetic activation of cholinergic neurons in BF subnuclei induces modality-selective desynchronization in specific sensory cortices, whereas activation of noradrenergic LC neurons induces broad desynchronization throughout multiple sensory cortices. Thus, we demonstrate a clear distinction in the organization and function of cholinergic BF and noradrenergic LC projections into primary sensory cortices: cholinergic BF neurons are highly selective in their projections and modulation of specific sensory cortices, whereas noradrenergic LC neurons broadly innervate and modulate multiple sensory cortices. SIGNIFICANCE STATEMENT: Neuromodulatory inputs from the basal forebrain (BF) and locus ceruleus (LC) are widespread in the mammalian cerebral cortex and are known to play important roles in attention and arousal, but little is known about the selectivity of their cortical projections. Using a dual retrobead tracing technique along with optogenetic stimulation, we have identified anatomic and functional differences in the way cholinergic BF neurons and noradrenergic LC neurons project into primary sensory cortices. While BF projections are highly selective to individual sensory cortices, LC projections diverge into multiple sensory cortices. To our knowledge, this is the first definitive proof that BF and LC projections to primary sensory cortices show both anatomic and functional differences in selectivity for modulating cortical activity.