Study proves Rapid Cortical Reorganization in V1

Cognitive Neuropsychology of Visual Perception

“Referred Visual Sensations”: Rapid Perceptual Elongation after Visual Cortical Deprivation


There have been many proposed hypotheses as to why and how perceptual distortion after deprivation occurs. Perceptual distortion in the in the human adult somatosensory system has been well studied however; researchers still don’t fully understand the consequences of deprivation in the visual system. In a previous study the authors examined a type of visual deprivation (elongation) observed in a stroke patient. Perceptual elongation in visual studies is the apparent increase in width or height of an object due to vision deprivation. The study provided ample evidence using fMRI to show that the perceptual elongation is a result of concomitant changes in V1 where deprived upper left visual field neurons now respond to stimuli in the lower left visual field. There were several limitations in the previous study that the authors adequately overcome in this paper in order to strengthen their findings.

Building on the previous study, the authors would like to answer if they can replicate the previous study’s findings in healthy individuals and also determine how soon after deprivation elongation occurs. To do this the authors used a one-eye patch technique to deprive bottom-up input to the blind spot region of the primary visual cortex (V1). The strength of this approach is that it is noninvasive (unlike the stroke case) and is reversible. Their reasoning in patching one eye is that the blind spot region of the unpatched eye will no longer be receiving input from the patched eye since the cortical representation of the blind spot of the left eye only receives information from the right eye. This is why the authors present visual stimuli (rectangles) only around the blind spot rather than at other locations in the visual field.  Paramount#00001

            Using five different experiments the authors’ results show that participants perceive rectangles adjacent to the deprived blind spot to be elongated toward the blind spot. This means that rectangles placed lateral to the blind spot appeared to widen whereas rectangles placed above and below appeared to increase in height. Using a probit analysis to determine the PSE, the magnitude of elongation was quantified. Their results show that rectangles 10% or shorter or narrower than a square would be perceived as squares rather than rectangles. Interestingly, the authors found that the magnitude of elongation increases with eccentricity meaning that elongation was greatest for the right side of the blind spot and weakest on the left side, which is closest to the fovea. In terms of the timing of perceptual elongation, these results held at both 10min and 2h of deprivation. In order to rule out the possibility that elongations are the result of reduced acuity for peripheral stimuli, the authors show that the magnitude of elongation decreases with increasing distance from the border of the deprived blind spot. To determine how quickly elongation occurs shape judgments were made at 2-min intervals, to which all time points after patching resulted in elongation especially within 2-min of first deprivation. More specifically in the next study, aspect ratio judgments were obtained and analyzed in 1-second time intervals for deprivation and nondeprivation. Again, participants perceived elongation within seconds of the onset of deprivation and showed reversal within seconds when the elongation ended.

There are two aspects of cortical representation that are important to define in order to appreciate the findings of this study.  A visual stimulus in a specific visual field location causes neurons in a specific cortical region to respond but also, that neural activity in that cortical region signals throughout the brain that a visual stimulus appeared in that visual field location. This neural activity causes a person to see the stimulus regardless of whether or not a stimulus actually appeared there. There a several possible forms of cortical reorganization that can occur. For example let’s assume that cortical region A now represents visual field location Y instead of location X. One possibility is that a visual stimulus at location Y will result in a cortical response in A that signals to brain areas that something appears at X.  Another is that a visual stimulus at location Y will result in a cortical response in A that signals to brain areas that something appears at Y. Lastly a visual stimulus at location X will result in a cortical response in A that signals to brain areas that something appears at Y.

The authors provide an interesting hypothesis as to how this observed rapid and reversible visual elongation occurs. They suggest that perceptual elongations are due to rapid receptive field expansion after deprivation. Their hypothesis is strongly supported by electrophysiological studies that show after minutes of deprivation, the V1 neurons will now respond to stimuli that normally would only activate adjacent cortex. Moreover, the underlying neural mechanism has to be an “unmasking” of already existing connections because the observed “referred visual sensations” are far too fast to be due to growth of new dendrites/synapses. In terms of cortical representation, it was assumed that by patching an eye loss of visual input from the patched eye (by deafferentation) means that that visual information no longer innervates the cortical region for the blind spot of the unpatched eye.  Patching effectively removes this bottom-up input to a region of cortex. The synaptic connections and innervations still exist however the loss of visual information results in cortical reorganization, which is why elongation is observed. Neural activity in that blind spot cortical region is now activated by adjacent blind spot stimuli, which signal throughout the brain that the rectangle is taller or wider than in actuality.

Overall the authors provide convincing evidence for visual elongation after cortical deprivation and credible arguments as to how and why these referred visual sensations occur. However some limitations and weaknesses exist in their study. Experimentally they show occurrence of perceptual elongation around the deprived blind spots and show that these occur within seconds of deprivation. The authors significantly build on previous studies by studying the time scale for cortical reorganization to occur. Evidence of such rapid cortical reorganization was one of the most interesting findings in the study given the typical length of time needed for cortical reorganization in previous studies. Without such rapid changes in receptive field properties the authors wouldn’t have been able to assertively state that the underlying neural mechanism is an unmasking of preexisting conditions.  I thought the authors’ application of their results to other contradictory cases of long-term reorganization of visual cortex was fair; they state that cortical reorganization differences in these other cases may be occurring over longer timescales or may even include some structural changes in cortex. They adequately disregard several alternate hypotheses such as the perceptual filling-in explanation. I thought their methodology in determining the blind spot in each subject was accurate since it was highly reproducible. However, there were too few available response choices in describing the rectangles. Participants could only state whether the stimulus was thinner than a square, a square, or wider than a square. Despite the simplicity, the study generated sufficient and convincing quantitative results.  In future studies they should examine fMRI responses to specific areas within the blind spot, which would highly strengthen their findings.

How our Brain Synchronizes to the Sun

A diversity of paracrine signals sustains molecular circadian cycling in suprachiasmatic nucleus circuits

Maywood & Hastings Synopsis


Circadian regulating SCN neurons were once thought of as autonomous transcriptional/translational feedback oscillators. However, pacemaking in the SCN is now understood to be reliant on mutually dependent intra and intercellular processing.  Understanding how this circadian information is actually communicated across SCN circuits will help us interpret the mammalian molecular clock, a function that coordinates many daily physiological processes such as behavior and metabolism.

The authors used varying genetic conditions of host and graft SCN neurons, in combination with pharmacological manipulations to show that paracrine signaling is sufficient to restore circadian rhythm in VIP and VIP-receptor deficient SCN neurons. They were also able to show that a hierarchy of factors drives SCN paracrine coordination.

The authors’ work provides convincing evidence that nonsynaptic paracrine factors (VIP, GRP, AVP) are responsible for the rapid activation of VIP deficient SCN. Moreover, the authors posit that interneuronal signaling via VIP/VPAC2 appears to have a crucial role in setting pacemaker period.  The authors had to rule out the possibility that restoration of circadian gene expression does not, of itself, prove that the observed rhythm is simply dependent on rhythmic cues from the graft. I thought the authors could have excluded this possibility more effectively.  Future studies should investigate whether other essential paracrine factors exist that contribute to synchronized cellular pacemaking, other than VIP, GRP, and AVP. (In the absence of core transcriptional feedback loop elements).

I thought Figure 4 was the most interesting figure of the paper because it showed how cellular pacemaking is most dependent on VIPergic signaling. But in its absence, SCN circadian gene expression is dependent on AVP and GRP-mediated signaling, with GRP cues being slightly less important than AVP cues.

Stressed Out? Neuroscience explains why

Stress-induced priming of glutamate synapses unmasks associative short-term plasticity

Kuzmiski and Bains Synopsisimg-article-are-you-too-stressed-out

Changes in glutamatergic synaptic plasticity has been hypothesized as critical to stress-induced priming in the hypothalamic-pituitary-adrenal axis.  Understanding how stress induced behavioral and neuroendocrine sensitization occurs will allow researchers to better comprehend how stress in modulated within the HPA axis and may provide potential clinical treatments for stress disorders.

The authors used whole-cell patch clamp recordings from PNCs to first show that NMDA:AMPA ratio is directly correlated with immobilization stress (IMO). Since IMO decreased the frequency of NMDAR mediated spontaneous EPSCs without affecting amplitude it was hypothesized that IMO induces LTD of NMDAR currents. Moreover bath application of CRH significantly depressed NMDAR eEPSCs while leaving amplitude and PPR of AMPAR currents unaltered. To determine the mechanism of action, the authors applied HFS to glutamate afferents after CRH, which resulted in robust STP with coincident decrease in PPR and increase in CV. The authors could then conclude that this was a glutamatergic presynaptic effect.  Figure 3 shows that IMO-HFS induced STP was similar (in duration and magnitude) to exogenous application of CRH.  In order to determine that CRH is necessary for acute stress priming of glutamate synapses the authors used a CRHR1 antagonist, which prevented STP following IMO as well as bath application of CRH.  To prove that STP is unmasked by blocking NMDARs the authors used a noncompetitive open channel antagonist (MK801).  Next the authors tested various theories of specific mechanisms of action. Their results support mediation by multivesicular glutamate release or even that SNARE-dependent exocytosis interferes with NMDAR trafficking.

The authors work not only shows that decreases in NMDAR function following IMO and CRH affects activity dependent changes in synaptic transmission but postulates a specific mechanism by which changes in NMDARs unmasks STP.   Even though the exact mechanism may be unclear their findings reliably show that depression of NMDAR currents by stress or CRH unmasks activity dependent STP. Also, inhibitory retrograde messaging is likely to be involved in restraining HFS-induced STP. I thought that the authors overlooked the potential role of AMPA receptor trafficking in PNCs. Even though they showed that BoNT/C and SNAP-25 does not interfere with AMPA recycling (amplitude of sEPSCs do not change), there could still be a dual role of AMPAR and NMDARs in multivesicular release. Regardless their results show a prominent and convincing role of changes in NMDAR trafficking that result in STP unmasking. Future studies should examine the exact mechanism as to why depression of NMDAr currents by either stress or CRH unmasks activity-dependent STP. Although the authors provide a convincing hypothesis they are still unclear as to exactly how the STP is unmasked.

I thought Figure 5 was the best figure in the paper because it convincingly showed how STP is exactly unmasked. The previous figures build necessary introductory evidence to show how STP is due to changes in NMDARs but this figure specifically and accurately identifies several likely mechanism of action such as the inhibition of SNARE-dependent exocytosis.

Why we are Fat: How the Lateral Hypothalamus controls Feeding

 Inhibitory Circuit Architecture of the Lateral Hypothalamus Orchestrates Feeding

Jennings et. al Synopsis


The lateral hypothalamus has been implicated as a crucial neural substrate for motivated behavior, in particular feeding. However the precise neurocircuit elements for control of feeding and its reinforcement are relatively unknown. Importantly, dysfunction of these particular neural circuits may be responsible for maladaptive feeding behaviors and potentially contribute to worldwide obesity epidemics.

The authors were particularly interested in testing the inhibitory synaptic inputs from the BNST (bed nucleus of the stria terminalis) that innervate the glutamatergic neurons of the lateral hypothalamus. The authors targeted Cre-inducible viral construct coding for Channelrhodopsin2 fused with yellow fluorescent protein. Using in-vivo photostimulation of Vgat^BNSTàLH, optogenetic activation produced voracious feeding in well-fed mice. In terms of the motivational valence, mice showed place preference for the photostimulation-paired chamber. Also preference for high-fat food suggests the BNSTàLH circuit elicits feeding that is preferential for calorie dense substances. Conversely, photoinhibition (using inhibitory opsin archaerhodopsin) diminishes feeding even in food-deprived mice and is aversive. To characterize the molecular phenotype of the postsynaptic LH neuronal targets that receie Vgat^BNSTàLH innervation, photostimulation was paired with multiplexed gene expression of individual LH neurons. Their results show that BNST-GABAergic inputs form strong connections with postsynaptic LH neurons that have higher levels of Vglut2. Conversely, weakly innervated LH neurons showed higher levels of Vgat expression.  To confirm these results they used Vglut2-ires-Cre and Vgat-ires-Cre mice (ires rabies-virus tracing technique, labeling: FLEX-TVA-mCherrry in LH and SADG-GFP in BNST), which again showed that significantly more BNST neurons innervate LH glutamatergic neurons compared to LH GABAergic neurons.

The authors’ work reliably supports the hypothesis that inhibitory inputs from the BNST specifically innervate and suppress LH glutamatergic neurons to promote feeding. In order to strengthen their findings related to the importance of the lateral hypothalamus in feeding, they could have looked at other neuronal populations that innervate the LH besides the BNST. They showed how photoactivation of the Vgat^BNSTàVentral tegmental area did not elicit feeding behavior, but this was the only other area explored. Future studies could also look at projection targets of LH glutamatergic neurons for ways to intervene in obesity/ behavioral overeating.

I thought Figure 2 was the most interesting figure because it provided the most convincing evidence of how important inhibitory innervation of the LH by the BNST promotes feeding. Figure 2 shows that the inhibition of these crucial feeding pathways causes diminished feeding even in rats that were food-deprived. This alone demonstrates that in promoting feeding BNST innervation of the LH is crucial.



Hot Ladies: Female Body Temperature Control

Central control of Fever and Female Body Temperature by RANKL/RANK

Hanada and Leibbrandt Synopsis


Osteoclast differentiation factors RANKL/RANK have been implicated in regulation of bone remodeling, lymph node organogenesis, and mammary gland lactation. However their homeostatic role in the CNS and interplay between pro inflammatory cytokines and prostaglandins has been relatively unknown.

The authors methodically tested the functional relevance of RANKL/RANK in the brain by performing stereotactic intracerebroventricular injections. These injections induced responses such as high fever, hyperthermia, or ACTH increases showing that RANKL can trigger fever in the CNS.  Next, immunostaining and c-Fos studies showed RANK expression in key thermoregulation areas of the brain namely the preoptic area, the medialseptal nucleus, lateral septal nucleus, VMH, DMH, PVN, and SCN. In order to genetically confirm the role of RANK/RANKL in a fever response they used tissue specific knockout mice (Nestin-Cre rank-floxed) to show that genetic inactivation of RANK nullifies fever response to RANKL since RANK expression on astrocytes is required to induce fever. RANK’s role in LPS induced fever was examined using LPS i.p. injections which showed pro inflammatory cytokine response followed by induction of Rankl/Rank mRNA in the POA/MSn/LSn. Finally, using female NEstin-Cre and GFAP-Cre rank-floxed mice, increased basal body temperatures show female thermoregulatory control as an important function of RANK/RANKL.

The author’s work provides ample evidence that RANK/RANKL not only control key fever induced responses in the brain but also activate brain regions involved in thermoregulation. These differentiation factors are crucial because RANK/RANKL knockout mice show defective fever inducing systems.

I thought that the correlation between the two Turkish children with RANK mutations and their exhibited impairment to producing fever during pneumonia could have been caused by other factors besides RANK influence (possibly other downstream effects) that resulted in their mutation. This could be studied further. I was also curious why loss of RANK in male rice had no effect on basal circadian body temperatures. Future studies could examine differences in ovarian sex hormones as to why this occurs.

Figure 4 is the most relevant and significant figure because it shows how GFAP-cre and Nestin-Cre rank^floxed mice produce significant decreases in average female body temperatures which I thought was the major objective of the paper/study.

How Melanopsin Cells contribute to Photoentrainment and PLR

Melanopsin cells are the principal conduits for rod-cone input to non-image forming vision

Güler Synopsis


Mammals are dependent on rod-cone light information to support pattern vision and non-image-forming functions such as circadian photoentrainment and pupillary light reflex.  Determining how ipRGCs relay rod-cone light information can help elucidate which retinal outputs support pattern vision versus non-image-forming functions.

The authors used genetically ablated ipRGCs (no longer intrinsically photosensitive) in mice to show that mice lacking ipRGCs maintain pattern vision but still show deficits in PLR and circadian photoentrainment. Moreover, these deficits are more extensive than the melanopsin knockouts.

The authors’ work provides the intriguing hypothesis that ipRGCs are only modulatory in normal vision since loss of ipRGCs does not influence image formation. However in the case of irradiance-dependent NIF functions, these are substantially impaired in ipRGC knockouts.   This paper relied on wheel running behavior for photoentrainment studies but the authors could have used another method to show how circadian photoentrainment was impaired.   Future studies should investigate subpopulations of ipRGCs to show how morphological differences innervate different brain regions to perform distinct light-induced functions.

I thought figure 4 was the most interesting figure of the paper because it showed that Opn4 mutants do not photoentrain or mask to the 24-h light/dark cycle, which is significant because it shows how the mutants were completely blind to the light shift whereas wild type mice synchronized with the shifted cycle.


Male Hormones: The Battle between Testosterone and Estrogen


Estrogen Masculinizes Neural Pathways and Sex-Specific Behavior

Wu Synopsis 

Sex hormones such as estrogen and testosterone are essential for various sex-specific behaviors for both males and females. How these two sex hormones interact and their dependence on aromatase in sexual differentiation and dimorphism has been relatively unknown. Understanding the aromatization of testosterone into estrogen may help elucidate which neural circuits control certain male behaviors.

To characterize the expression of aromatase (which may show where testosterone is converted to estrogen) the authors used homologous recombination in ES cells to insert an IRES-plap-IRES-lacZ reporter into aromatase locus. Beta-galactosidase activity reveals sparse aromatase distribution throughout the BNST, MEA, and POA. Labeling for PLAP activity reveals sex differences such as a richer plexus of fibers in the BNST and MeA in males and in the caudal hypothalamus for females. In the AH and VMH, PLAP-labeled fibers occupy a larger volume in males than in females. The authors also determined that masculinization of aromatase pathways does not require testosterone signaling through AR since the number of betagal-postive neurosn in the BNST, MeA, and caudal hypothalamus is similar between Tfm (loss of function allele of x-linked AR) and WT males.  To determine whether estrogen is sufficient to masculinize aromatase expression in females the authors showed that it can be induced by neonatal estrogen.  The authors wanted to know if sexual dimorphisms in the BNST and MeA resulted from sex-specific apoptosis. What they discovered was that estrogen promotes cells survival in these areas. Giving estrogen to female pups reduces cell death whereas abrogation of estrogen of estrogen synthesis increases apoptosis in males.

The authors’ work provides convincing evidence that aromatization of testosterone into estrogen plays a critical role in both developing aromatase neural pathways as well as activating male territorial behaviors. They first reveal differences in number and projections of aromatase-positive neurons.  Their work suggests that the cellular mechanism of estrogen is one that is promotes cell survival and promotes sexual differentiation in a positive feedback manner.

I thought they left an important question unanswered. They couldn’t determine the relevance of dimorphisms in aromatase-positive neurons to male territorial behaviors. They postulate that these neurons are directly involved in the circuits that control male behaviors or may serve as dimorphic neuroendocrine sources of estrogen. Future studies should investigate these specific sex differences to understand why these dimorphisms exist within aromatase positive neurons.

I thought Figure 6 was most interesting because it gave the authors an unexpected result.  They show that estrogen masculinizes territorial but not sexual behavior. The authors provide an interesting hypothesis as to why estrogen controls only territorial behavior, which guides a large part of the discussion.