Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(−/y)). METHODS: We recorded from the CA1 in Fmr1(−/y) and WT littermates over six 10-min exploration sessions in a novel environment—three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(−/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(−/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(−/y) rats. These findings were consistent with increased excitability of Fmr1(−/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(−/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(−/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(−/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13229-022-00528-z

Imbalance of flight-freeze responses and their cellular correlates in the Nlgn3-/y rat model of autism

Abstract Background Mutations in the postsynaptic transmembrane protein neuroligin-3 are highly correlative with autism spectrum disorders (ASDs) and intellectual disabilities (IDs). Fear learning is well studied in models of these disorders, however differences in fear response behaviours are often overlooked. We aim to examine fear behaviour and its cellular underpinnings in a rat model of ASD/ID lacking Nlgn3. Methods This study uses a range of behavioural tests to understand differences in fear response behaviour in Nlgn3 −/y rats. Following this, we examined the physiological underpinnings of this in neurons of the periaqueductal grey (PAG), a midbrain area involved in flight-or-freeze responses. We used whole-cell patch-clamp recordings from ex vivo PAG slices, in addition to in vivo local-field potential recordings and electrical stimulation of the PAG in wildtype and Nlgn3 −/y rats. We analysed behavioural data with two- and three-way ANOVAS and electrophysiological data with generalised linear mixed modelling (GLMM). Results We observed that, unlike the wildtype, Nlgn3 −/y rats are more likely to response with flight rather than freezing in threatening situations. Electrophysiological findings were in agreement with these behavioural outcomes. We found in ex vivo slices from Nlgn3 −/y rats that neurons in dorsal PAG (dPAG) showed intrinsic hyperexcitability compared to wildtype. Similarly, stimulating dPAG in vivo revealed that lower magnitudes sufficed to evoke flight behaviour in Nlgn3 −/y than wildtype rats, indicating the functional impact of the increased cellular excitability. Limitations Our findings do not examine what specific cell type in the PAG is likely responsible for these phenotypes. Furthermore, we have focussed on phenotypes in young adult animals, whilst the human condition associated with NLGN3 mutations appears during the first few years of life. Conclusions We describe altered fear responses in Nlgn3 −/y rats and provide evidence that this is the result of a circuit bias that predisposes flight over freeze responses. Additionally, we demonstrate the first link between PAG dysfunction and ASD/ID. This study provides new insight into potential pathophysiologies leading to anxiety disorders and changes to fear responses in individuals with ASD

Modelling human choices: MADeM and decision‑making

Research supported by FAPESP 2015/50122-0 and DFG-GRTK 1740/2. RP and AR are also part of the Research, Innovation and Dissemination Center for Neuromathematics FAPESP grant (2013/07699-0). RP is supported by a FAPESP scholarship (2013/25667-8). ACR is partially supported by a CNPq fellowship (grant 306251/2014-0)

Neo-Lamarckianism and the Davisian cycle of erosion

Les idées de W. M. Davis ont fait partie de la formation de la plupart des géomorphologues américains et britanniques, mais le cadre conceptuel dans lequel elles ont été développées n’a que rarement été exploré. En particulier, on a omis de reconnaître que les idées de Davis sur l’évolution des paysages n’ont pas été formulées dans le cadre d’une interprétation darwinienne, comme cela a été parfois hâtivement affirmé, mais plutôt dans celui d’une interprétation néo-lamarckienne, qui était dominante aux États-Unis au tournant du XXe siècle. Un des concepts les plus importants de l’interprétation néo-lamarckienne de l’évolution est celui de récapitulation dans le développement des organismes biologiques. Après une présentation des principes fondamentaux du néo-lamarckisme et de son adaptation par les savants américains de cette époque, cet article explore l’œuvre de Davis pour démontrer comment ces idées ont imprégné son interprétation de l’évolution des paysages terrestres.The ideas of W. M. Davis have formed a part of the education of most American and British geomorphologists, but the conceptual framework within which they were developed has rarely been properly explored. In this paper the origins of Davis’s cycle of erosion are discussed in the context of the neo-lamarckian evolutionary ideas that were then prevalent in America. In particular, it is not generally acknowledged that Davis’s ideas of landscape evolution were not formed in the context the Darwinian interpretation, but rather, were formulated in the context of a neo-Lamarckian interpretation, which was the dominant one held in the America of his time. Important within the neo-Lamarckian interpretation of evolution was the idea of recapitulation. After introducing the ideas underlying American neo-Lamarckianism, this paper explores the writings of Davis to demonstrate how these ideas informed his interpretation of landscape evolution

The use of historical photography in environmental studies

The time-scales over which significant environmental changes take place can vary from a few hours on highly mobile coastal sediments to tens or even hundreds of years on exposed stone surfaces. Studies of rapidly changing features can be carried out using traditional field monitoring techniques, perhaps aided by airborne or satellite imagery if the scale of change is sufficiently large. Less dynamic surfaces do not lend themselves to such methods since, over the time-scale of traditional research projects, the amount of change will be less than the known errors in the measurement techniques. This paper describes the use of historical aerial photographs to study changes in an inter-tidal environment, around Langstone Harbour and Chichester Harbour (U.K.), and discusses the advantages and limitations of this data source

The use of historical photography in environmental studies

The time-scales over which significant environmental changes take place can vary from a few hours on highly mobile coastal sediments to tens or even hundreds of years on exposed stone surfaces. Studies of rapidly changing features can be carried out using traditional field monitoring techniques, perhaps aided by airborne or satellite imagery if the scale of change is sufficiently large. Less dynamic surfaces do not lend themselves to such methods since, over the time-scale of traditional research projects, the amount of change will be less than the known errors in the measurement techniques. This paper describes the use of historical aerial photographs to study changes in an inter-tidal environment, around Langstone Harbour and Chichester Harbour (U.K.), and discusses the advantages and limitations of this data source