Biology subjects

Herzog, L. E.

Publications and source records attributed to Herzog, L. E..

4 recordsLinked to original sources

bioRxiv2022

Brain region-specific changes in neurons and glia and dysregulation of dopamine signaling in Grin2a mutant mice

Schizophrenia disease mechanisms remain poorly understood, in large part due to a lack of valid animal models. Rare heterozygous loss-of-function mutations in GRIN2A, encoding a subunit of the NMDA (N-methyl-d-aspartate) receptor, greatly increase the risk of schizophrenia. By transcriptomic, proteomic, electroencephalogram (EEG) recording and behavioral analysis, we report that heterozygous Grin2a mutant mice show: (i) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes, oligodendrocytes); (ii) evidence of reduced activity in prefrontal cortex and increased activity in hippocampus and striatum; (iii) elevated dopamine signaling in striatum; (iv) altered cholesterol biosynthesis in astrocytes; (v) reduction of glutamatergic receptor signalin g proteins in the synapse; (iv) heightened gamma oscillation power in EEG; (vi) aberrant locomotor behavioral pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of schizophrenia, and underscore the utility of Grin2a-deficient mice as a new genetic model of schizophrenia.

neuroscience↗

bioRxiv2022

Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients

BACKGROUNDSchizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disorder [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? METHODSWe monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. RESULTSGrin2a and Akap11 mutants exhibited increased resting gamma power, attenuated 40-50 Hz auditory steady-state responses (ASSR), and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. CONCLUSIONSThe EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.

neuroscience↗

bioRxiv2019

Reorganization and reactivation of a preexisting taste-responsive hippocampal network

Animals need to remember the locations of nourishing and toxic food sources for survival, a fact that necessitates a mechanism for associating taste experiences with particular places. We have previously identified such responses within hippocampal place cells [1], the activity of which is thought to aid memory-guided behavior by forming a mental map of an animals environment that can be reshaped through experience [2-7]. It remains unknown, however, whether taste-responsiveness is intrinsic to a subset of place cells, or emerges as a result of experience that reorganizes spatial maps. Here, we recorded from neurons in the dorsal CA1 region of rats running for palatable tastes delivered via intra-oral cannulae at specific locations on a linear track. We identified a subset of taste-responsive cells that, even prior to taste exposure, had larger place fields than non-taste-responsive cells overlapping with stimulus delivery zones. Taste-responsive cells place fields then contracted, as a result of taste experience, leading to a stronger representation of stimulus delivery zones on the track. Taste-responsive units exhibited increased sharp-wave ripple co-activation during the taste delivery session and subsequent rest periods, which correlated with the degree of place field contraction. Our results reveal that novel taste experience evokes responses within a preconfigured network of taste-responsive hippocampal place cells with large fields, whose spatial representations are refined by sensory experience to signal areas of behavioral salience. This represents a possible mechanism by which animals identify and remember locations where ecologically relevant stimuli are found within their environment.

neuroscience↗

bioRxiv2018

Interaction of taste and place coding in the hippocampus

An animals survival depends on finding food, and the memory of food and contexts are often linked. Given that the hippocampus is required for spatial and contextual memory, it is reasonable to expect related coding of space and food stimuli in hippocampal neurons. However, relatively little is known about how the hippocampus responds to tastes, the most central sensory property of food. In this study, we examined the taste-evoked responses and spatial firing properties of single units in the dorsal CA1 hippocampal region as male rats received a battery of taste stimuli differing in both chemical composition and palatability within a specific spatial context. We identified a subset of hippocampal neurons that responded to tastes, some of which were place cells. These taste and place responses had a distinct interaction: taste-responsive cells tended to have less spatially specific firing fields, and place cells only responded to tastes delivered inside their place field. Like neurons in the amygdala and lateral hypothalamus, hippocampal neurons discriminated between tastes predominantly on the basis of palatability, with taste-selectivity emerging concurrently with palatability-relatedness; these responses did not reflect movement or arousal. However, hippocampal taste responses emerged several hundred msec later than responses in other parts of the taste system, suggesting that the hippocampus does not influence real-time taste decisions, instead associating the hedonic value of tastes with a particular context. This incorporation of taste responses into existing hippocampal maps could be one way that animals use past experience to locate food sources.\n\nSignificance statementFinding food is essential for animals survival, and taste and context memory are often linked. While hippocampal responses to space and contexts have been well characterized, little is known about how the hippocampus responds to tastes. Here, we identified a subset of hippocampal neurons that discriminated between tastes based on palatability. Cells with stronger taste responses typically had weaker spatial responses, and taste responses were confined to place cells firing fields. Hippocampal taste responses emerged later than in other parts of the taste system, suggesting that the hippocampus does not influence taste decisions, but rather, associates the hedonic value of tastes consumed within a particular context. This could be one way that animals use past experience to locate food sources.

neuroscience↗