Past events

While our world is three-dimensional (3D), spatial perception is most often studied in animals and humans navigating across 2D surfaces. I will present two cases in which the consideration of the 3D nature of the world has led us to surprising results. The first case regards the neural recording of mammalian grid cells. Grid cells that are recorded over 2D surfaces create a hexagonal-shaped repetitive lattice, which inspired many theoretical studies to investigate the pattern’s mechanism and function. Upon recording in bats flying through 3D space, we found that grid cells did not exhibit a hexagonal global lattice, but rather showed a local order – with grid-fields exhibiting fixed local distances. Our results in 3D strongly argue against most of the prevailing models of grid-cell function, and we suggest a unified model that explains the results in both 2D and 3D.  The second case regards the perception of 3D space in humans. Different behavioral studies have shown contradicting evidence of human perception of 3D space being either isotropic or vertically compressed. We addressed this question using human experts in 3D motion and navigation – fighter pilots – studied in a flight simulator. We considered two aspects of the perception of 3D space: surrounding space and travelled space. We show that different aspects of the perception of space are shaped differently with experience: whereas the perception of the 3D surrounding space was vertically compressed in both expert and non-expert subjects, fighter pilots exhibited isotropic perception of travelled space, whereas non-expert subjects retained a distorted perception.  Together, our research sheds light on the differences and similarities between the coding of 3D versus 2D space, in both animals and humans.  

Rats (if trained appropriately) can apply to some set of tactile stimuli a multitude of different perceptual and memory capacities. For instance, they can express working memory, where the most recent stimulus has to be stored and retrieved to support a comparison to the ongoing stimulus. They can express reference memory, where the ongoing stimulus has to be compared to some stable, internal boundary. They can change that internal boundary as a function of stimulus statistics. They can learn to ignore stimuli of the same sensory modality, if untagged by an acoustic cue. While it might seem easiest to draw up computational/functional frameworks tailor-made to each behavior, we are trying to explain several different behaviors by common algorithms. This informal discussion will mainly present ongoing psychophysical studies, with a few preliminary physiological added here and there.  

Dahlia Kushinsky- Daily normalization of E/I-ratio by light-driven transcription maintains visual processing Abstract: Consistent and reliable encoding of sensory information is essential for an animal’s survival. However, sensory input in an animal’s environment is constantly changing, likely resulting in changes in the brain at the level of molecules, synapses, and cellular circuitry. It is therefore unclear which elements of the system are stable or dynamic, and what mechanisms allow for overall stability of the brain throughout an animal’s life. To address this question, we focused on the visual cortex of adult mice and took advantage of the daily sensory transitions from the dark of night to daylight and back to darkness during a single day. By using RNA-seq, patch clamp slice electrophysiology, and in vivo longitudinal calcium imaging in awake mice, we monitor the light driven changes in molecules, synapses, and cells across a single day. At each of these levels (molecular, synaptic, and cellular), we find rapid sensory-driven increases shortly after transition from darkness to light which is then normalized later in the day. Based on these findings, we suggest that sensory-driven genetic changes maintain functional stability of neural circuits by regulating E/I ratio in excitatory neurons every day. Michael Sokoletsy- Isolated correlates of perception in the posterior cortex Abstract: To uncover the neural mechanisms of stimulus perception, experimenters commonly use tasks in which subjects are repeatedly presented with a weak stimulus and instructed to report, via movement, if they perceived the stimulus. The difference in neural activity between reported stimulus (hit) and unreported stimulus (miss) trials is then seen as potentially perception-related. However, recent studies found that activity related to the report spreads throughout the brain, calling into question to what extent such tasks may be conflating activity that is perception-related with activity that is report-related. To isolate perception-related activity, we developed a paradigm in which the same mice were trained to report either the presence or absence of a whisker stimulus. We found that isolated perception-related activity appeared within a posterio-parietal network of cortical regions contralateral to the stimulus, was on average an order of magnitude lower than the hit versus miss difference, and began just after the low-level stimulus response. In addition, we performed controls to check that it is specifically associated with performance and is not the result of differences in time or uninstructed movements across the tasks. In summary, we revealed for the first time in mice the cortical areas that are associated specifically with the perception of a sensory stimulus and independently of the report.

The immune system and the gut microbiome are becoming major players in chronic neurodegenerative conditions. One of the key interfaces between the brain and the immune system with an impact on brain function is the choroid plexus (CP). The CP interface is central to the maintenance of brain homeostasis by exerting a plethora of different biological processes. However, in aging and Alzheimer’s disease (AD), interferon type-I (IFN-I) signaling accumulates at the CP and impedes part of its beneficial function by inducing a CP-pro-aging signature. My research contributed to the finding that IFN-I signaling at the CP induces an aging-like signature in microglia and impedes cognitive abilities in middle-aged mice in a microglia-dependent manner. In addition, I demonstrated that the brain-specific enzyme, cholesterol 24-hydroxylase (CYP46A1), is expressed by the CP epithelium and that its product, 24-hydroxycholesterol (24-OH), downregulates CP-pro-inflammatory signatures. Furthermore, in AD, CP CYP46A1 protein levels were decreased in both mice and humans and overexpression of Cyp46a1 at the CP in 5xFAD mice reversed brain inflammation, microglial dysfunction signatures, and cognitive loss. Finally, while the pro-inflammatory cytokine TNF-α impaired CP Cyp46a1 expression in vitro, boosting systemic immunity in vivo increased its levels in an IFNGR2-dependent manner. These results highlight CYP46A1 at the CP as a remote regulator of brain inflammation, which diminishes with neurodegeneration, but is amenable to rescue. Focusing on the gut microbiome, I found that 5xFAD mice devoid of microbiome exhibited a striking decrease of long-term spatial memory deficit and increased synaptic and neuronal survival. Spatial memory deficit in 5xFAD mice kept in germ free (GF) or specific-pathogen free (SPF) conditions, negatively correlated with the abundance of 2-hydroxypyridine, while systemic, chronic supply of 2-hydroxypyridine in SPF 5xFAD mice improved spatial memory deficits in comparison to phosphate-buffered saline (PBS)-supplied 5xFAD mice. Overall, these findings demonstrate a microbiome-dependent effect on AD pathology in the 5xFAD mouse model and suggest a connection between 2-hydroxypyridine and AD manifestation. In general, this research thesis addresses novel aspects of choroid plexus and gut microbiome metabolism and their relation to AD progression. Zoom link https://weizmann.zoom.us/j/98658552127?pwd=ZkZmWTBkd1AxZ0xPbGlpU3FPUWpzUT09 Meeting ID:986 5855 2127 Password:495213

Decision-making requires a consideration of both costs and benefits. Although mesolimbic dopamine (DA) plays an established role in reward-related decisions, there has been longstanding controversy over its sensitivity to costs vs benefits. Manipulations of DA function imply a primary role in mediating cost calculations, while DA recordings suggest a preference for encoding benefit. These studies often confound cost and benefit by varying both simultaneously, and rarely combine correlational and causal tools to explore how encoding relates to behavior. Here we independently varied costs and benefits, studying DA's role using both recording and manipulation. We found that DA release reflects changes in both cost and benefit, although the precise relationship depended on the time within a trial and the site of DA release. Then we used behavioral economics to probe how these patterns of DA release relate to two important behavioral parameters: a mouse's preferred level of reward consumption and the amount of work it is willing to expend to maintain that consumption. We found that DA release in the nucleus accumbens core and dorsolateral striatum does not predict an animal's preferred level of consumption. It does, however, strongly reflect an animal's willingness to work for reward. Surprisingly, the more DA released for each reward, the less demand for that reward. The inverse relationship between DA release and demand held true both for natural rewards and optogenetic stimulation of DA release in both striatal targets. Our findings support an inverted-U model of dopamine and reinforcement, where a minimal level of DA release is critical to motivate behavior, but increments above that level actually reduce demand. Link to join: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421

Advanced methods now allow fast, cellular-level recording of neural activity across the mammalian brain, enabling exploration of how brain-wide dynamical patterns might give rise to complex behavioral states, such as the clinically important state of dissociation. We established a dissociation-like state in mice, induced by administration of ketamine or phencyclidine. Large-scale neural recording revealed that these dissociative agents elicited a 1–3-Hz rhythm in layer 5 neurons of retrosplenial cortex, uncoupled from most other brain regions except thalamus. Additionally, using brain-wide intracranial electrical recording in a patient with focal epilepsy, the human experience of dissociation was linked to a similar ~3 Hz rhythm in posteromedial cortex (homologous to mouse retrosplenial cortex), and stimulation of this area induced dissociation.   

Investigating conscious intentions associated with spontaneous, voluntary action is challenging. Typical paradigms inherently lack the stimulus-response structure that is common in neuroscientific tasks (Haggard, 2019). Moreover, studying the onset of intentions has proven notoriously difficult, conceptually and empirically. Measuring the onset of intentions with a clock was shown to be inconsistent, biased, and unreliable (Maoz et al., 2015). Furthermore, probe methods estimated intention onset much earlier than clock-based methods (Matsuhashi & Hallett, 2008), complicating the reconciliation of these results. Some have even questioned the existence of intentions as discrete, causal neural states (Schurger & Utihol, 2015).

Two of the most fundamental questions of sensory neuroscience are: 1) how is stimulus information represented by neuronal activity? and 2) what features of this activity are read out to guide behavior? The first question has been the subject of a large body of work across different sensory modalities. The second question remains a significant challenge, since one needs to establish a causal link between neuronal activity and behavior. In olfaction, it has been proposed that information about odors is encoded in spatial distribution of receptor activation and the next level mitral/tufted cells, as well as in their relative timing and synchrony. However, the role of different features of neural activity in guiding behavior remains unknown. Using mouse olfaction as a model system, we developed both technological and conceptual approaches to study sensory coding by perturbing neural activity at different levels of information processing during sensory driven behavioral tasks. We developed methods for both one-photon spatiotemporal pattern stimulation using digital mirror devices at the glomerulus level in the olfactory bulb, and two-photon holographic pattern stimulation deeper in the brain, at the level of mitral/tufted cells. Using these techniques, we performed quantitative behavioral experiments to, first, measure psychophysical limits of the readability of different features of the neural code, and, second, to quantify their behavioral relevance. Based on these results, we built a detailed mathematical model of the behavioral relevance of the different features of spatiotemporal neural activity. Our approach can be potentially generalized to other sensory systems. Link: https://weizmann.zoom.us/j/95406893197?pwd=REt5L1g3SmprMUhrK3dpUDJVeHlrZz09 Meeting ID: 954 0689 3197 Password: 750421